Pharmacological modulation of chemokine receptor function

British Journal of Pharmacology

Volumn 165, Issue 6, 2012, Pages 1617-1643

  Scholten, D J ^a   Canals, M ^a,b   Maussang, D ^a   Roumen, L ^a   Smit, M J ^a   Wijtmans, M ^a   De Graaf, C ^a   Vischer, H F ^a   Leurs, R ^a  

^a VU UNIVERSITY AMSTERDAM   (Netherlands)

^b MONASH UNIVERSITY   (Australia)

Author keywords

allosterism; binding sites; chemokine receptors; crystal structures; dimerization; functional selectivity; G protein coupled receptors; ligand interactions; nanobody

Indexed keywords

1 [5 CHLORO 2 [2 [4 (4 FLUOROBENZYL) 2 METHYL 1 PIPERAZINYL] 2 OXOETHOXY]PHENYL]UREA; 4 [(4 BROMOPHENYL)(ETHOXYIMINO)METHYL] 1' [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4' METHYL 1,4' BIPIPERIDINE; 8 [(4 AMINOBUTYL)(2 BENZIMIDAZOLYLMETHYL)AMINO] 1,2,3,4 TETRAHYDROQUINOLINE; ANTINEOPLASTIC AGENT; APLAVIROC; BMS 397; CHEMOKINE RECEPTOR; CHEMOKINE RECEPTOR ANTAGONIST; HGS 004; JNJ 27141491; LMD 009; MARAVIROC; MLN 1202; MOGAMULIZUMAB; N [1,4,8,11 TETRAAZACYCLOTETRADECANYL 1,4 PHENYLENEBIS(METHYLENE)] 2 (AMINOMETHYL)PYRIDINE; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; NAVARIXIN; NBI 74330; PIPERIDINE; PLERIXAFOR; PRO 140; PYRAZINYL SULFONAMIDE DERIVATIVE; REPARIXIN; RS 504393; SB 265610; SB 282241; SB 332235; SB265610; SCH 361125; UCB 35625; UNCLASSIFIED DRUG; UNINDEXED DRUG; VICRIVIROC; VUF 10132; YM 370749; ZK 756326;

ALLOSTERISM; ALPHA HELIX; ATHEROSCLEROTIC CARDIOVASCULAR DISEASE; BINDING AFFINITY; BINDING SITE; CARBOXY TERMINAL SEQUENCE; CHEMOTAXIS; CRYSTAL STRUCTURE; DIMERIZATION; DRUG ANTAGONISM; DRUG DESIGN; DRUG RECEPTOR BINDING; DRUG STRUCTURE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYDROGEN BOND; IMMUNOMODULATION; IMMUNOSURVEILLANCE; LIGAND BINDING; METASTASIS; MULTIPLE SCLEROSIS; NONHUMAN; PERIPHERAL T CELL LYMPHOMA; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN MOTIF; REVIEW; T CELL LEUKEMIA; T CELL LYMPHOMA;

ANIMALS; BIOLOGICAL AGENTS; CHEMOKINES; DRUG DESIGN; HUMANS; RECEPTORS, CHEMOKINE;

EID: 81555213635     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2011.01551.x     Document Type: Review

References (206)

1. Ahuja S, Lee J, Murphy P, (1996). CXC chemokines bind to unique sets of selectivity determinants that can function independently and are broadly distributed on multiple domains of human interleukin-8 receptor B. Determinants of high affinity binding and receptor activation are distinct. J Biol Chem 271: 225-232.
2. Alexander SPH, Mathie A, Peters JA, (2011). Guide to Receptors and Channels (GRAC), 5th Edition. Br J Pharmacol 164 (Suppl. 1): S1-S324.
3. Allegretti M, Bertini R, Cesta M, Bizzarri C, Di Bitondo R, Di Cioccio V, et al,. (2005). 2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors. J Med Chem 48: 4312-4331.
4. Allen S, Crown S, Handel T, (2007). Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol 25: 787-820.
5. Andrews G, Jones C, Wreggett KA, (2008). An intracellular allosteric site for a specific class of antagonists of the CC chemokine G protein-coupled receptors CCR4 and CCR5. Mol Pharmacol 73: 855-867.
6. Arcemisbehere L, Sen T, Boudier L, Balestre MN, Gaibelet G, Detouillon E, et al,. (2010). Leukotriene BLT2 receptor monomers activate the G(i2) GTP-binding protein more efficiently than dimers. J Biol Chem 285: 6337-6347.
7. Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, Iizawa Y, et al,. (1999). A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA 96: 5698-5703.
8. Babcock GJ, Farzan M, Sodroski J, (2003). Ligand-independent dimerization of CXCR4, a principal HIV-1 coreceptor. J Biol Chem 278: 3378-3385.
9. Balkwill F, (2004). Cancer and the chemokine network. Nat Rev Cancer 4: 540-550.
10. Ballesteros JA, Weinstein H, (1995). [19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. In:, Stuart CS, (ed.). Methods in Neurosciences, Vol. 25. Academic Press: New York, pp. 366-428.
11. Bayry J, Tchilian EZ, Davies MN, Forbes EK, Draper SJ, Kaveri SV, et al,. (2008). In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination. Proc Natl Acad Sci USA 105: 10221-10226.
12. Becker OM, Marantz Y, Shacham S, Inbal B, Heifetz A, Kalid O, et al,. (2004). G protein-coupled receptors: in silico drug discovery in 3D. Proc Natl Acad Sci USA 101: 11304-11309.
13. Benkirane M, Jin DY, Chun RF, Koup RA, Jeang KT, (1997). Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5delta32. J Biol Chem 272: 30603-30606.
14. Berchiche YA, Gravel S, Pelletier M-E, St-Onge G, Heveker N, (2010). Different effects of the different natural CC-chemokine receptor 2B (CCR2B) ligands on {beta}-arrestin recruitment, G{alpha}i signalling, and receptor internalization. Mol Pharmacol 79: 488-498.
15. Berger EA, Murphy PM, Farber JM, (1999). Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 17: 657-700.
16. Berkhout T, Blaney F, Bridges A, Cooper D, Forbes I, Gribble A, et al,. (2003). CCR2: characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach. J Med Chem 46: 4070-4086.
17. Bertini R, Allegretti M, Bizzarri C, Moriconi A, Locati M, Zampella G, et al,. (2004). Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc Natl Acad Sci USA 101: 11791-11796.
18. Blanpain C, Doranz B, Bondue A, Govaerts C, De Leener A, Vassart G, et al,. (2003). The core domain of chemokines binds CCR5 extracellular domains while their amino terminus interacts with the transmembrane helix bundle. J Biol Chem 278: 5179-5187.
19. Bongers G, Maussang D, Muniz LR, Noriega VM, Fraile-Ramos A, Barker N, et al,. (2010). The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice. J Clin Invest 120: 3969-3978.
20. Bradley ME, Bond ME, Manini J, Brown Z, Charlton SJ, (2009). SB265610 is an allosteric, inverse agonist at the human CXCR2 receptor. Br J Pharmacol 158: 328-338.
21. Brelot A, Heveker N, Montes M, Alizon M, (2000). Identification of residues of CXCR4 critical for human immunodeficiency virus coreceptor and chemokine receptor activities. J Biol Chem 275: 23736-23744.
22. Buntinx M, Hermans B, Goossens J, Moechars D, Gilissen RAHJ, Doyon J, et al,. (2008). Pharmacological profile of JNJ-27141491 [(S)-3-[3,4-difluorophenyl) -propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl acid methyl ester], as a noncompetitive and orally active antagonist of the human chemokine receptor CCR2. J Pharmacol Exp Ther 327: 1-9.
23. Casarosa P, Menge WM, Minisini R, Otto C, van Heteren J, Jongejan A, et al,. (2003). Identification of the first nonpeptidergic inverse agonist for a constitutively active viral-encoded G protein-coupled receptor. J Biol Chem 278: 5172-5178.
24. Casarosa P, Waldhoer M, LiWang PJ, Vischer HF, Kledal T, Timmerman H, et al,. (2005). CC and CX3C chemokines differentially interact with the N terminus of the human cytomegalovirus-encoded US28 receptor. J Biol Chem 280: 3275-3285.
25. Chakera A, Seeber RM, John AE, Eidne KA, Greaves DR, (2008). The duffy antigen/receptor for chemokines exists in an oligomeric form in living cells and functionally antagonizes CCR5 signaling through hetero-oligomerization. Mol Pharmacol 73: 1362-1370.
26. Cherezov V, Rosenbaum D, Hanson M, Rasmussen S, Thian F, Kobilka T, et al,. (2007). High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318: 1258-1265.
27. Cherezov V, Abola E, Stevens RC, (2010). Recent progress in the structure determination of GPCRs, a membrane protein family with high potential as pharmaceutical targets. Methods Mol Biol 654: 141-168.
28. Cherney RJ, Nelson DJ, Lo YC, Yang G, Scherle PA, Jezak H, et al,. (2008). Synthesis and evaluation of cis-3,4-disubstituted piperidines as potent CC chemokine receptor 2 (CCR2) antagonists. Bioorg Med Chem Lett 18: 5063-5065.
29. Chien EYT, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, et al,. (2010). Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330: 1091-1095.
30. Christopoulos A, Kenakin T, (2002). G protein-coupled receptor allosterism and complexing. Pharmacol Rev 54: 323-374.
31. Clark-Lewis I, Mattioli I, Gong J, Loetscher P, (2003). Structure-function relationship between the human chemokine receptor CXCR3 and its ligands. J Biol Chem 278: 289-295.
32. Colvin R, Campanella G, Manice L, Luster A, (2006). CXCR3 requires tyrosine sulfation for ligand binding and a second extracellular loop arginine residue for ligand-induced chemotaxis. Mol Cell Biol 26: 5838-5849.
33. Contento RL, Molon B, Boularan C, Pozzan T, Manes S, Marullo S, et al,. (2008). CXCR4-CCR5: a couple modulating T cell functions. Proc Natl Acad Sci USA 105: 10101-10106.
34. Cox MA, Jenh CH, Gonsiorek W, Fine J, Narula SK, Zavodny PJ, et al,. (2001). Human interferon-inducible 10-kDa protein and human interferon-inducible T cell alpha chemoattractant are allotopic ligands for human CXCR3: differential binding to receptor states. Mol Pharmacol 59: 707-715.
35. Davies MN, Bayry J, Tchilian EZ, Vani J, Shaila MS, Forbes EK, et al,. (2009). Toward the discovery of vaccine adjuvants: coupling in silico screening and in vitro analysis of antagonist binding to human and mouse CCR4 receptors. PLoS ONE 4: e8084.
36. De Clercq E, (2003). The bicyclam AMD3100 story. Nat Rev Drug Discov 2: 581-587.
37. De Clercq E, (2010). Recent advances on the use of the CXCR4 antagonist plerixafor (AMD3100, Mozobil.,¢) and potential of other CXCR4 antagonists as stem cell mobilizers. Pharmacol Ther 128: 509-518.
38. Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, et al,. (1996). Identification of a major co-receptor for primary isolates of HIV-1. Nature 381: 661-666.
39. Deupi X, Olivella M, Govaerts C, Ballesteros J, Campillo M, Pardo L, (2004). Ser and Thr residues modulate the conformation of pro-kinked transmembrane {alpha}-helices. Biophys J 86: 105-115.
40. Dorsch S, Klotz KN, Engelhardt S, Lohse MJ, Bunemann M, (2009). Analysis of receptor oligomerization by FRAP microscopy. Nat Methods 6: 225-230.
41. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, et al,. (1996). HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381: 667-673.
42. Dragic T, Trkola A, Thompson D, Cormier E, Kajumo F, Maxwell E, et al,. (2000). A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci USA 97: 5639-5644.
43. El-Asmar L, Springael JY, Ballet S, Andrieu EU, Vassart G, Parmentier M, (2005). Evidence for negative binding cooperativity within CCR5-CCR2b heterodimers. Mol Pharmacol 67: 460-469.
44. Feng Y, Broder CC, Kennedy PE, Berger EA, (1996). HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272: 872-877.
45. Fernandez E, Lolis E, (2002). Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol 42: 469-499.
46. Fonseca JM, Lambert NA, (2009). Instability of a class a G protein-coupled receptor oligomer interface. Mol Pharmacol 75: 1296-1299.
47. Galandrin S, Oligny-Longpré G, Bouvier M, (2007). The evasive nature of drug efficacy: implications for drug discovery. Trends Pharmacol Sci 28: 423-430.
48. Gerlach L, Skerlj R, Bridger G, Schwartz T, (2001). Molecular interactions of cyclam and bicyclam non-peptide antagonists with the CXCR4 chemokine receptor. J Biol Chem 276: 14153-14160.
49. Ghassabeh GH, Muyldermans S, Saerens D, (2010). Nanobodies, single-domain antigen-binding fragments of camelid heavy-chain antibodies. In:, Shire SJ, et al. (eds.). Current Trends in Monoclonal Antibody Development and Manufacturing. Springer: New York, pp. 29-48.
50. Gilbert J, Lekstrom-Himes J, Donaldson D, Lee Y, Hu M, Xu J, et al,. (2011). Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region. Am J Cardiol 107: 906-911.
51. Gong J, Clark-Lewis I, (1995). Antagonists of monocyte chemoattractant protein 1 identified by modification of functionally critical NH2-terminal residues. J Exp Med 181: 631-640.
52. Gonsiorek W, Fan X, Hesk D, Fossetta J, Qiu H, Jakway J, et al,. (2007). Pharmacological characterization of 2-Hydroxy-N,N- dimethyl-3-{2-[-[(R)-1-(5- methyl-furan-2-yl)-propyl]amino]-3,4- dioxo-cyclobut-1-enylamino}-benzamide (Sch527123), a potent allosteric CXCR1/CXCR2 antagonist. J Pharmacol Exp Ther 322: 477-485.
53. Gorry PR, Zhang C, Wu S, Kunstman K, Trachtenberg E, Phair J, et al,. (2002). Persistence of dual-tropic HIV-1 in an individual homozygous for the CCR5 delta 32 allele. Lancet 359: 1832-1834.
54. Govaerts C, Blanpain C, Deupi X, Ballet S, Ballesteros J, Wodak S, et al,. (2001). The TXP motif in the second transmembrane helix of CCR5. A structural determinant of chemokine-induced activation. J Biol Chem 276: 13217-13225.
55. Govaerts C, Bondue A, Springael J, Olivella M, Deupi X, Le Poul E, et al,. (2003). Activation of CCR5 by chemokines involves an aromatic cluster between transmembrane helices 2 and 3. J Biol Chem 278: 1892-1903.
56. de Graaf C, Rognan D, (2009). Customizing G Protein-coupled receptor models for structure-based virtual screening. Curr Pharm Des 15: 4026-4048.
57. de Graaf C, Foata N, Engkvist O, Rognan D, (2008). Molecular modeling of the second extracellular loop of G-protein coupled receptors and its implication on structure-based virtual screening. Proteins 71: 599-620.
58. Gupta S, Pillarisetti K, Thomas R, Aiyar N, (2001). Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1alpha: implications for development of selective CXCR4 antagonists. Immunol Lett 78: 29-34.
59. Hall SE, Mao A, Nicolaidou V, Finelli M, Wise EL, Nedjai B, et al,. (2009). Elucidation of binding sites of dual antagonists in the human chemokine receptors CCR2 and CCR5. Mol Pharmacol 75: 1325-1336.
60. Handel TM, Horuk R, (2010). Duffy antigen inhibitors: useful therapeutics for malaria? Trends Parasitol 26: 329-333.
61. Haskell C, Horuk R, Liang M, Rosser M, Dunning L, Islam I, et al,. (2006). Identification and characterization of a potent, selective nonpeptide agonist of the CC chemokine receptor CCR8. Mol Pharmacol 69: 309-316.
62. Hatse S, Huskens D, Princen K, Vermeire K, Bridger G, de Clercq E, et al,. (2007). Modest human immunodeficiency virus coreceptor function of CXCR3 is strongly enhanced by mimicking the CXCR4 ligand binding pocket in the CXCR3 receptor. J Virol 81: 3632-3639.
63. Hatse S, Princen K, Vermeire K, Gerlach L-O, Rosenkilde MM, Schwartz TW, et al,. (2003). Mutations at the CXCR4 interaction sites for AMD3100 influence anti-CXCR4 antibody binding and HIV-1 entry. FEBS Lett 546: 300-306.
64. Haworth B, Lin H, Fidock M, Dorr P, Strange P, (2007). Allosteric effects of antagonists on signalling by the chemokine receptor CCR5. Biochem Pharmacol 74: 891-897.
65. Hern JA, Baig AH, Mashanov GI, Birdsall B, Corrie JE, Lazareno S, et al,. (2010). Formation and dissociation of M1 muscarinic receptor dimers seen by total internal reflection fluorescence imaging of single molecules. Proc Natl Acad Sci USA 107: 2693-2698.
66. Hernanz-Falcon P, Rodriguez-Frade JM, Serrano A, Juan D, del Sol A, Soriano SF, et al,. (2004). Identification of amino acid residues crucial for chemokine receptor dimerization. Nat Immunol 5: 216-223.
67. Hutchings CJ, Koglin M, Marshall FH, (2010). Therapeutic antibodies directed at G protein-coupled receptors. MAbs 2: 594-606.
68. Ishii T, Ishida T, Utsunomiya A, Inagaki A, Yano H, Komatsu H, et al,. (2010). Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma. Clin Cancer Res 16: 1520-1531.
69. Isik N, Hereld D, Jin T, (2008). Fluorescence resonance energy transfer imaging reveals that chemokine-binding modulates heterodimers of CXCR4 and CCR5 receptors. PLoS ONE 3: e3424.
70. Issafras H, Angers S, Bulenger S, Blanpain C, Parmentier M, Labbe-Jullie C, et al,. (2002). Constitutive agonist-independent CCR5 oligomerization and antibody-mediated clustering occurring at physiological levels of receptors. J Biol Chem 277: 34666-34673.
71. Jaakola V-P, Griffith MT, Hanson MA, Cherezov V, Chien EYT, Lane JR, et al,. (2008). The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322: 1211-1217.
72. Jacobson JM, Saag MS, Thompson MA, Fischl MA, Liporace R, Reichman RC, et al,. (2008). Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults. J Infect Dis 198: 1345-1352.
73. Jacobson JM, Lalezari JP, Thompson MA, Fichtenbaum CJ, Saag MS, Zingman BS, et al,. (2010a). Phase 2a study of the CCR5 monoclonal antibody PRO 140 administered intravenously to HIV-infected adults. Antimicrob Agents Chemother 54: 4137-4142.
74. Jacobson JM, Thompson MA, Lalezari JP, Saag MS, Zingman BS, D'Ambrosio P, et al,. (2010b). Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a CCR5 monoclonal antibody. J Infect Dis 201: 1481-1487.
75. Jähnichen S, Blanchetot C, Maussang D, Gonzalez-Pajuelo M, Chow KY, Bosch L, et al,. (2010). CXCR4 nanobodies (VHH-based single variable domains) potently inhibit chemotaxis and HIV-1 replication and mobilize stem cells. Proc Natl Acad Sci USA 107: 20565-20570.
76. Jekle A, Keppler OT, De Clercq E, Schols D, Weinstein M, Goldsmith MA, (2003). In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4-mediated killing of uninfected CD4 T cells. J Virol 77: 5846-5854.
77. Jensen PC, Nygaard R, Thiele S, Elder A, Zhu G, Kolbeck R, et al,. (2007). Molecular interaction of a potent nonpeptide agonist with the chemokine receptor CCR8. Mol Pharmacol 72: 327-340.
78. Jensen PC, Thiele S, Ulven T, Schwartz TW, Rosenkilde MM, (2008). Positive versus negative modulation of different endogenous chemokines for CC-chemokine receptor 1 by small molecule agonists through allosteric versus orthosteric binding. J Biol Chem 283: 23121-23128.
79. Jin H, Shen X, Baggett BR, Kong X, LiWang PJ, (2007). The human CC chemokine MIP-1beta dimer is not competent to bind to the CCR5 receptor. J Biol Chem 282: 27976-27983.
80. Jones SW, Brockbank SM, Mobbs ML, Le Good NJ, Soma-Haddrick S, Heuze AJ, et al,. (2006). The orphan G-protein coupled receptor RDC1: evidence for a role in chondrocyte hypertrophy and articular cartilage matrix turnover. Osteoarthritis Cartilage 14: 597-608.
81. Kalatskaya I, Berchiche YA, Gravel S, Limberg BJ, Rosenbaum JS, Heveker N, (2009). AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol Pharmacol 75: 1240-1247.
82. Kehrl JH, Hwang IY, Park C, (2009). Chemoattract receptor signaling and its role in lymphocyte motility and trafficking. Curr Top Microbiol Immunol 334: 107-127.
83. Kellenberger E, Springael J-Y, Parmentier M, Hachet-Haas M, J-l G, Rognan D, (2007). Identification of nonpeptide CCR5 receptor agonists by structure-based virtual screening. J Med Chem 50: 1294-1303.
84. Kenakin T, (2010a). Functional selectivity and biased receptor signaling. J Pharmacol Exp Ther 336: 296-302.
85. Kenakin T, (2010b). G protein coupled receptors as allosteric proteins and the role of allosteric modulators. J Recept Signal Transduct Res 30: 313-321.
86. Kenakin T, Miller LJ, (2010). Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol Rev 62: 265-304.
87. Kim JH, Lim JW, Lee SW, Kim K, No KT, (2011). Ligand supported homology modeling and docking evaluation of CCR2: docked pose selection by consensus scoring. J Mol Model DOI: 10.1007/s00894-010-0943-x.
88. Klibanov OM, (2009). Vicriviroc, a CCR5 receptor antagonist for the potential treatment of HIV infection. Curr Opin Investig Drugs 10: 845-859.
89. Kofuku Y, Yoshiura C, Ueda T, Terasawa H, Hirai T, Tominaga S, et al,. (2009). Structural basis of the interaction between chemokine stromal cell-derived factor-1/CXCL12 and its G-protein-coupled receptor CXCR4. J Biol Chem 284: 35240-35250.
90. Kohout T, Nicholas S, Perry S, Reinhart G, Junger S, Struthers R, (2004). Differential desensitization, receptor phosphorylation, beta-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. J Biol Chem 279: 23214-23222.
91. Kondru R, Zhang J, Ji C, Mirzadegan T, Rotstein D, Sankuratri S, et al,. (2008). Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists. Mol Pharmacol 73: 789-800.
92. Kouroumalis A, Nibbs R, Aptel H, Wright K, Kolios G, Ward S, (2005). The chemokines CXCL9, CXCL10, and CXCL11 differentially stimulate G alpha i-independent signaling and actin responses in human intestinal myofibroblasts. J Immunol 175: 5403-5411.
93. Kraneveld AD, Braber S, Overbeek S, de Kruijf P, Koelink P, Smit MJ, (2011). Chemokine receptors in inflammatory diseases. In:, Smit MJ, Lira SA, Leurs R, (eds). Chemokine Receptors as Drug Targets, Vol. 46. Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, pp. 107-150.
94. de Kruijf P, van Heteren J, Lim H, Conti P, van der Lee M, Bosch L, et al,. (2009). Nonpeptidergic allosteric antagonists differentially bind to the CXCR2 chemokine receptor. J Pharmacol Exp Ther 329: 783-790.
95. Kufareva I, Rueda M, Katritch V, Participants of GPCR Dock 2010 (Box 1), Stevens RC, Abagyan R, (2011). Status of GPCR modeling and docking as reflected by community wide GPCR Dock 2010 assessment. Structure (In press).
96. Kuszak AJ, Pitchiaya S, Anand JP, Mosberg HI, Walter NG, Sunahara RK, (2009). Purification and functional reconstitution of monomeric mu-opioid receptors: allosteric modulation of agonist binding by Gi2. J Biol Chem 284: 26732-26741.
97. Lalezari J, Yadavalli GK, Para M, Richmond G, Dejesus E, Brown SJ, et al,. (2008). Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1-infected patients. J Infect Dis 197: 721-727.
98. Lau EK, Paavola CD, Johnson Z, Gaudry JP, Geretti E, Borlat F, et al,. (2004). Identification of the glycosaminoglycan binding site of the CC chemokine, MCP-1: implications for structure and function in vivo. J Biol Chem 279: 22294-22305.
99. Laurence JS, Blanpain C, Burgner JW, Parmentier M, LiWang PJ, (2000). CC chemokine MIP-1 beta can function as a monomer and depends on Phe13 for receptor binding. Biochemistry 39: 3401-3409.
100. Leach K, Charlton S, Strange P, (2007). Analysis of second messenger pathways stimulated by different chemokines acting at the chemokine receptor CCR5. Biochem Pharmacol 74: 881-890.
101. Levoye A, Balabanian K, Baleux F, Bachelerie F, Lagane B, (2009). CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood 113: 6085-6093.
102. Liu Y, Zhou E, Yu K, Zhu J, Zhang Y, Xie X, et al,. (2008). Discovery of a novel CCR5 antagonist lead compound through fragment assembly. Molecules 13: 2426-2441.
103. Lohse MJ, (2010). Dimerization in GPCR mobility and signaling. Curr Opin Pharmacol 10: 53-58.
104. Luker KE, Gupta M, Luker GD, (2009). Imaging chemokine receptor dimerization with firefly luciferase complementation. FASEB J 23: 823-834.
105. Mack M, Luckow B, Nelson PJ, Cihak J, Simmons G, Clapham PR, et al,. (1998). Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity. J Exp Med 187: 1215-1224.
106. Maeda K, Das D, Ogata-Aoki H, Nakata H, Miyakawa T, Tojo Y, et al,. (2006). Structural and molecular interactions of CCR5 inhibitors with CCR5. J Biol Chem 281: 12688-12698.
107. Maeda K, Das D, Yin PD, Tsuchiya K, Ogata-Aoki H, Nakata H, et al,. (2008). Involvement of the second extracellular loop and transmembrane residues of CCR5 in inhibitor binding and HIV-1 fusion: insights into the mechanism of allosteric inhibition. J Mol Biol 381: 956-974.
108. Maeda K, Nakata H, Koh Y, Miyakawa T, Ogata H, Takaoka Y, et al,. (2004). Spirodiketopiperazine-Based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. J Virol 78: 8654-8662.
109. Maeda DY, Quinn MT, Schepetkin IA, Kirpotina LN, Zebala JA, (2010). Nicotinamide glycolates antagonize CXCR2 activity through an intracellular mechanism. J Pharmacol Exp Ther 332: 145-152.
110. Mantovani A, (1999). The chemokine system: redundancy for robust outputs. Immunol Today 20: 254-257.
111. Mantovani A, Bonecchi R, Locati M, (2006). Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat Rev Immunol 6: 907-918.
112. Maussang D, Langemeijer E, Fitzsimons CP, Stigter-van Walsum M, Dijkman R, Borg MK, et al,. (2009). The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res 69: 2861-2869.
113. May L, Leach K, Sexton P, Christopoulos A, (2007). Allosteric modulation of G protein-coupled receptors. Annu Rev Pharmacol Toxicol 47: 1-51.
114. Mellado M, Rodriguez-Frade JM, Vila-Coro AJ, Fernandez S, Martin de Ana A, Jones DR, et al,. (2001). Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. EMBO J 20: 2497-2507.
115. de MendonÃa F, da Fonseca P, Phillips R, Saldanha J, Williams T, Pease J, (2005). Site-directed mutagenesis of CC chemokine receptor 1 reveals the mechanism of action of UCB 35625, a small molecule chemokine receptor antagonist. J Biol Chem 280: 4808-4816.
116. Milligan G, (2009). G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function. Br J Pharmacol 158: 5-14.
117. Milligan G, (2010). The role of dimerisation in the cellular trafficking of G-protein-coupled receptors. Curr Opin Pharmacol 10: 23-29.
118. Mirzadegan T, Diehl F, Ebi B, Bhakta S, Polsky I, McCarley D, et al,. (2000). Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within the helical bundle. J Biol Chem 275: 25562-25571.
119. Molon B, Gri G, Bettella M, Gomez-Mouton C, Lanzavecchia A, Martinez AC, et al,. (2005). T cell costimulation by chemokine receptors. Nat Immunol 6: 465-471.
120. Monteclaro FS, Charo IF, (1996). The amino-terminal extracellular domain of the MCP-1 receptor, but not the RANTES/MIP-1alpha receptor, confers chemokine selectivity. Evidence for a two-step mechanism for MCP-1 receptor activation. J Biol Chem 271: 19084-19092.
121. Moriconi A, Cesta M, Cervellera M, Aramini A, Coniglio S, Colagioia S, et al,. (2007). Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2. J Med Chem 50: 3984-4002.
122. Muniz-Medina VM, Jones S, Maglich JM, Galardi C, Hollingsworth RE, Kazmierski WM, et al,. (2009). The relative activity of 'function sparing' HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property? Mol Pharmacol 75: 490-501.
123. Murphy PM, Charo IF, Hills R, Horuk R, Matsushima K, Oppenheim JJ, (2011). Chemokine receptors. IUPHAR database (IUPHAR-DB), available at: http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=14.
124. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, et al,. (1996). Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382: 635-638.
125. Nelson AL, Dhimolea E, Reichert JM, (2010). Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 9: 767-774.
126. Nicholls DJ, Tomkinson NP, Wiley KE, Brammall A, Bowers L, Grahames C, et al,. (2008). Identification of a putative intracellular allosteric antagonist binding-site in the CXC chemokine receptors 1 and 2. Mol Pharmacol 74: 1193-1202.
127. Nijmeijer S, Leurs R, Smit MJ, Vischer HF, (2010). The Epstein-Barr virus-encoded G protein-coupled receptor BILF1 hetero-oligomerizes with human CXCR4, scavenges Galphai proteins, and constitutively impairs CXCR4 functioning. J Biol Chem 285: 29632-29641.
128. Niwa R, Shoji-Hosaka E, Sakurada M, Shinkawa T, Uchida K, Nakamura K, et al,. (2004). Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Res 64: 2127-2133.
129. Nygaard R, Valentin-Hansen L, Mokrosinski J, Frimurer TM, Schwartz TW, (2010). Conserved water-mediated hydrogen bond network between TM-I, -II, -VI, and -VII in 7TM receptor activation. J Biol Chem 285: 19625-19636.
130. O'Hayre M, Salanga CL, Handel TM, Allen SJ, (2008). Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment. Biochem J 409: 635-649.
131. Olson WC, Jacobson JM, (2009). CCR5 monoclonal antibodies for HIV-1 therapy. Curr Opin HIV AIDS 4: 104-111.
132. Olson WC, Rabut GE, Nagashima KA, Tran DN, Anselma DJ, Monard SP, et al,. (1999). Differential inhibition of human immunodeficiency virus type 1 fusion, gp120 binding, and CC-chemokine activity by monoclonal antibodies to CCR5. J Virol 73: 4145-4155.
133. Oppermann M, Mack M, Proudfoot A, Olbrich H, (1999). Differential effects of CC chemokines on CC chemokine receptor 5 (CCR5) phosphorylation and identification of phosphorylation sites on the CCR5 carboxyl terminus. J Biol Chem 274: 8875-8885.
134. Ott T, Pahuja A, Nickolls S, Alleva D, Struthers R, (2004). Identification of CC chemokine receptor 7 residues important for receptor activation. J Biol Chem 279: 42383-42392.
135. Pakianathan DR, Kuta EG, Artis DR, Skelton NJ, Hebert CA, (1997). Distinct but overlapping epitopes for the interaction of a CC-chemokine with CCR1, CCR3 and CCR5. Biochemistry 36: 9642-9648.
136. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, et al,. (2000). Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289: 739-745.
137. Parenty G, Appelbe S, Milligan G, (2008). CXCR2 chemokine receptor antagonism enhances DOP opioid receptor function via allosteric regulation of the CXCR2-DOP receptor heterodimer. Biochem J 412: 245-256.
138. Pease J, Wang J, Ponath P, Murphy P, (1998). The N-terminal extracellular segments of the chemokine receptors CCR1 and CCR3 are determinants for MIP-1alpha and eotaxin binding, respectively, but a second domain is essential for efficient receptor activation. J Biol Chem 273: 19972-19976.
139. Pello OM, Martinez-Munoz L, Parrillas V, Serrano A, Rodriguez-Frade JM, Toro MJ, et al,. (2008). Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for immune response regulation. Eur J Immunol 38: 537-549.
140. Percherancier Y, Berchiche YA, Slight I, Volkmer-Engert R, Tamamura H, Fujii N, et al,. (2005). Bioluminescence resonance energy transfer reveals ligand-induced conformational changes in CXCR4 homo- and heterodimers. J Biol Chem 280: 9895-9903.
141. Perez-Nueno VI, Pettersson S, Ritchie DW, Borrell JI, Teixido J, (2009). Discovery of novel HIV entry inhibitors for the CXCR4 receptor by prospective virtual screening. J Chem Inf Model 49: 810-823.
142. Pin JP, Neubig R, Bouvier M, Devi L, Filizola M, Javitch JA, et al,. (2007). International union of basic and clinical pharmacology. LXVII. Recommendations for the recognition and nomenclature of G protein-coupled receptor heteromultimers. Pharmacol Rev 59: 5-13.
143. Proudfoot AE, (2008). Is CCR2 the right chemokine receptor to target in rheumatoid arthritis? Arthritis Rheum 58: 1889-1891.
144. Proudfoot A, Power C, Hoogewerf A, Montjovent M, Borlat F, Offord R, et al,. (1996). Extension of recombinant human RANTES by the retention of the initiating methionine produces a potent antagonist. J Biol Chem 271: 2599-2603.
145. Proudfoot AE, Handel TM, Johnson Z, Lau EK, LiWang P, Clark-Lewis I, et al,. (2003). Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proc Natl Acad Sci USA 100: 1885-1890.
146. Proudfoot AEI, Power CA, Schwarz MK, (2010). Anti-chemokine small molecule drugs: a promising future? Expert Opin Investig Drugs 19: 345-355.
147. Rajagopal S, Kim J, Ahn S, Craig S, Lam CM, Gerard NP, et al,. (2010). Beta-arrestin- but not G protein-mediated signaling by the 'decoy' receptor CXCR7. Proc Natl Acad Sci USA 107: 628-632.
148. Rajagopalan L, Rajarathnam K, (2004). Ligand selectivity and affinity of chemokine receptor CXCR1. Role of N-terminal domain. J Biol Chem 279: 30000-30008.
149. Reis RI, Santos EL, Pesquero JB, Oliveira L, Schanstra JP, Bascands JL, et al,. (2007). Participation of transmembrane proline 82 in angiotensin II AT1 receptor signal transduction. Regul Pept 140: 32-36.
150. Richter R, Casarosa P, Standker L, Munch J, Springael JY, Nijmeijer S, et al,. (2009). Significance of N-terminal proteolysis of CCL14a to activity on the chemokine receptors CCR1 and CCR5 and the human cytomegalovirus-encoded chemokine receptor US28. J Immunol 183: 1229-1237.
151. Ridker PM, (2007). C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 49: 2129-2138.
152. Rodriguez-Frade JM, Vila-Coro AJ, de Ana AM, Albar JP, Martinez AC, Mellado M, (1999). The chemokine monocyte chemoattractant protein-1 induces functional responses through dimerization of its receptor CCR2. Proc Natl Acad Sci USA 96: 3628-3633.
153. Rodriguez-Frade JM, del Real G, Serrano A, Hernanz-Falcon P, Soriano SF, Vila-Coro AJ, et al,. (2004). Blocking HIV-1 infection via CCR5 and CXCR4 receptors by acting in trans on the CCR2 chemokine receptor. EMBO J 23: 66-76.
154. Rosenkilde M, Gerlach L, Jakobsen J, Skerlj R, Bridger G, Schwartz T, (2004). Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor: transfer of binding site to the CXCR3 receptor. J Biol Chem 279: 3033-3041.
155. Rosenkilde M, Andersen M, Nygaard R, Frimurer T, Schwartz T, (2007a). Activation of the CXCR3 chemokine receptor through anchoring of a small molecule chelator ligand between TM-III, -IV, and -VI. Mol Pharmacol 71: 930-941.
156. Rosenkilde MM, Gerlach L-O, Hatse S, Skerlj RT, Schols D, Bridger GJ, et al,. (2007b). Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor. J Biol Chem 282: 27354-27365.
157. Rosenkilde MM, Benned-Jensen T, Frimurer TM, Schwartz TW, (2010). The minor binding pocket: a major player in 7TM receptor activation. Trends Pharmacol Sci 31: 567-574.
158. Sabroe I, Peck M, Van Keulen B, Jorritsma A, Simmons G, Clapham P, et al,. (2000). A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J Biol Chem 275: 25985-25992.
159. Sachpatzidis A, Benton B, Manfredi J, Wang H, Hamilton A, Dohlman H, et al,. (2003). Identification of allosteric peptide agonists of CXCR4. J Biol Chem 278: 896-907.
160. Saita Y, Kodama E, Orita M, Kondo M, Miyazaki T, Sudo K, et al,. (2006). Structural basis for the interaction of CCR5 with a small molecule, functionally selective CCR5 agonist. J Immunol 177: 3116-3122.
161. Salchow K, Bond ME, Evans SC, Press NJ, Charlton SJ, Hunt PA, et al,. (2010). A common intracellular allosteric binding site for antagonists of the CXCR2 receptor. Br J Pharmacol 159: 1429-1439.
162. Satoh M, Iida S, Shitara K, (2006). Non-fucosylated therapeutic antibodies as next-generation therapeutic antibodies. Expert Opin Biol Ther 6: 1161-1173.
163. Schrama D, Reisfeld RA, Becker JC, (2006). Antibody targeted drugs as cancer therapeutics. Nat Rev Drug Discov 5: 147-159.
164. Schulte A, Schulz B, Andrzejewski MG, Hundhausen C, Mletzko S, Achilles J, et al,. (2007). Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases. Biochem Biophys Res Commun 358: 233-240.
165. Seibert C, Ying W, Gavrilov S, Tsamis F, Kuhmann S, Palani A, et al,. (2006). Interaction of small molecule inhibitors of HIV-1 entry with CCR5. Virology 349: 41-54.
166. Shamovsky I, de Graaf C, Alderin L, Bengtsson M, Bladh H, Borjesson L, et al,. (2009). Increasing selectivity of CC chemokine receptor 8 antagonists by engineering nondesolvation related interactions with the intended and off-target binding sites. J Med Chem 52: 7706-7723.
167. Slinger E, Maussang D, Schreiber A, Siderius M, Rahbar A, Fraile-Ramos A, et al,. (2010). HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci Signal 3: ra58.
168. Smolarek D, Bertrand O, Czerwinski M, Colin Y, Etchebest C, de Brevern AG, (2010). Multiple interests in structural models of DARC transmembrane protein. Transfus Clin Biol 17: 184-196.
169. Sohy D, Parmentier M, Springael JY, (2007). Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers. J Biol Chem 282: 30062-30069.
170. Sohy D, Yano H, de Nadai P, Urizar E, Guillabert A, Javitch JA, et al,. (2009). Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the protean effects of 'selective' antagonists. J Biol Chem 284: 31270-31279.
171. Springael JY, Le Minh PN, Urizar E, Costagliola S, Vassart G, Parmentier M, (2006). Allosteric modulation of binding properties between units of chemokine receptor homo- and hetero-oligomers. Mol Pharmacol 69: 1652-1661.
172. Staudinger R, Wang X, Bandres JC, (2001). Allosteric regulation of CCR5 by guanine nucleotides and HIV-1 envelope. Biochem Biophys Res Commun 286: 41-47.
173. Stroke I, Cole A, Simhadri S, Brescia M, Desai M, Zhang J, et al,. (2006). Identification of CXCR3 receptor agonists in combinatorial small-molecule libraries. Biochem Biophys Res Commun 349: 221-228.
174. Stupple PA, Batchelor DV, Corless M, Dorr PK, Ellis D, Fenwick DR, et al,. (2010). An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: the discovery of N-{(1S)-1-(3-Fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl- 2-methyl-4,5,6,7-te trahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1] oct-8-yl] propyl}acetamide (PF-232798). J Med Chem 54: 67-77.
175. Surgand J-S, Rodrigo J, Kellenberger E, Rognan D, (2006). A chemogenomic analysis of the transmembrane binding cavity of human G-protein-coupled receptors. Proteins 62: 509-538.
176. Tanaka T, Nomura W, Narumi T, Masuda A, Tamamura H, (2010). Bivalent ligands of CXCR4 with rigid linkers for elucidation of the dimerization state in cells. J Am Chem Soc 132: 15899-15901.
177. Tchernychev B, Ren Y, Sachdev P, Janz JM, Haggis L, O'Shea A, et al,. (2010). Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells. Proc Natl Acad Sci USA 107: 22255-22259.
178. Thoma G, Streiff MB, Kovarik J, Glickman F, Wagner T, Beerli C, et al,. (2008). Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo. J Med Chem 51: 7915-7920.
179. Tian Y, New D, Yung L, Allen R, Slocombe P, Twomey B, et al,. (2004). Differential chemokine activation of CC chemokine receptor 1-regulated pathways: ligand selective activation of Galpha 14-coupled pathways. Eur J Immunol 34: 785-795.
180. Toth PT, Ren D, Miller RJ, (2004). Regulation of CXCR4 receptor dimerization by the chemokine SDF-1alpha and the HIV-1 coat protein gp120: a fluorescence resonance energy transfer (FRET) study. J Pharmacol Exp Ther 310: 8-17.
181. Tsibris A, Kuritzkes D, (2007). Chemokine antagonists as therapeutics: focus on HIV-1. Annu Rev Med 58: 445-459.
182. Tsukamoto H, Sinha A, DeWitt M, Farrens DL, (2010). Monomeric rhodopsin is the minimal functional unit required for arrestin binding. J Mol Biol 399: 501-511.
183. Vaidehi N, Schlyer S, Trabanino R, Floriano W, Abrol R, Sharma S, et al,. (2006). Predictions of CCR1 chemokine receptor structure and BX 471 antagonist binding followed by experimental validation. J Biol Chem 281: 27613-27620.
184. Veldkamp CT, Seibert C, Peterson FC, De la Cruz NB, Haugner JC 3rd, Basnet H, et al,. (2008). Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12. Sci Signal 1: ra4.
185. Venkatesan S, Petrovic A, Van Ryk DI, Locati M, Weissman D, Murphy PM, (2002). Reduced cell surface expression of CCR5 in CCR5Delta 32 heterozygotes is mediated by gene dosage, rather than by receptor sequestration. J Biol Chem 277: 2287-2301.
186. Vergunst CE, Gerlag DM, Lopatinskaya L, Klareskog L, Smith MD, van den Bosch F, et al,. (2008). Modulation of CCR2 in rheumatoid arthritis: a double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum 58: 1931-1939.
187. Verzijl D, Storelli S, Scholten DJ, Bosch L, Reinhart TA, Streblow DN, et al,. (2008). Noncompetitive antagonism and inverse agonism as mechanism of action of nonpeptidergic antagonists at primate and rodent CXCR3 chemokine receptors. J Pharmacol Exp Ther 325: 544-555.
188. Vila-Coro AJ, Rodriguez-Frade JM, Martin De Ana A, Moreno-Ortiz MC, Martinez AC, Mellado M, (1999). The chemokine SDF-1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. FASEB J 13: 1699-1710.
189. Vila-Coro AJ, Mellado M, Martin de Ana A, Lucas P, del Real G, Martinez AC, et al,. (2000). HIV-1 infection through the CCR5 receptor is blocked by receptor dimerization. Proc Natl Acad Sci USA 97: 3388-3393.
190. Viola A, Luster AD, (2008). Chemokines and their receptors: drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol 48: 171-197.
191. Waldhoer M, Fong J, Jones RM, Lunzer MM, Sharma SK, Kostenis E, et al,. (2005). A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc Natl Acad Sci USA 102: 9050-9055.
192. Walsh G, (2010). Biopharmaceutical benchmarks 2010. Nat Biotechnol 28: 917-924.
193. Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, et al,. (2008). Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 454: 486-491.
194. Watson C, Jenkinson S, Kazmierski W, Kenakin T, (2005). The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. Mol Pharmacol 67: 1268-1282.
195. Weiss RA, Clapham PR, (1996). Hot fusion of HIV. Nature 381: 647-648.
196. Whorton MR, Bokoch MP, Rasmussen SG, Huang B, Zare RN, Kobilka B, et al,. (2007). A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein. Proc Natl Acad Sci USA 104: 7682-7687.
197. Wilson S, Wilkinson G, Milligan G, (2005). The CXCR1 and CXCR2 receptors form constitutive homo- and heterodimers selectively and with equal apparent affinities. J Biol Chem 280: 28663-28674.
198. Wise E, Duchesnes C, da Fonseca P, Allen R, Williams T, Pease J, (2007). Small molecule receptor agonists and antagonists of CCR3 provide insight into mechanisms of chemokine receptor activation. J Biol Chem 282: 27935-27943.
199. Wong RSY, Bodart V, Metz M, Labrecque J, Bridger G, Fricker SP, (2008). Comparison of the potential multiple binding modes of bicyclam, monocylam, and noncyclam small-molecule CXC chemokine receptor 4 inhibitors. Mol Pharmacol 74: 1485-1495.
200. Wood A, Armour D, (2005). The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS. Prog Med Chem 43: 239-271.
201. Wu L, Ruffing N, Shi X, Newman W, Soler D, Mackay CR, et al,. (1996). Discrete steps in binding and signaling of interleukin-8 with its receptor. J Biol Chem 271: 31202-31209.
202. Wu B, Chien EYT, Mol CD, Fenalti G, Liu W, Katritch V, et al,. (2010). Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330: 1066-1071.
203. Xanthou G, Williams T, Pease J, (2003). Molecular characterization of the chemokine receptor CXCR3: evidence for the involvement of distinct extracellular domains in a multi-step model of ligand binding and receptor activation. Eur J Immunol 33: 2927-2936.
204. Zhang Y, Gilliam A, Maitra R, Damaj MI, Tajuba JM, Seltzman HH, et al,. (2010). Synthesis and biological evaluation of bivalent ligands for the cannabinoid 1 receptor. J Med Chem 53: 7048-7060.
205. Zhao J, Ben L, Wu Y, Hu W, Ling K, Xin S, et al,. (1999). Anti-HIV agent trichosanthin enhances the capabilities of chemokines to stimulate chemotaxis and G protein activation, and this is mediated through interaction of trichosanthin and chemokine receptors. J Exp Med 190: 101-111.
206. Zidar D, Violin J, Whalen E, Lefkowitz R, (2009). Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands. Proc Natl Acad Sci USA 106: 9649-9654.