Recent advances in the rationale design of GPER ligands

Current Medicinal Chemistry

Volumn 19, Issue 36, 2012, Pages 6199-6206

  Rosano, C ^a   Lappano, R ^b   Santolla, M F ^b   Ponassi, M ^a   Donadini, A ^a   Maggiolini, M ^b  

^a UNIVERSITY OF GENOA   (Italy)

^b UNIVERSITY OF CALABRIA   (Italy)

Author keywords

"In silico" docking simulations; Agonists antagonists; Antiestrogens; Atomic structures; Binding modes; Estrogens; GPCRs; GPR30 GPER; Homology modelling; Receptor; Small molecules ligands; Virtual screening

Indexed keywords

ESTROGEN RECEPTOR; G PROTEIN COUPLED RECEPTOR 30;

COMPUTER MODEL; MOLECULAR DOCKING; NONHUMAN; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN STRUCTURE; REVIEW; SEQUENCE HOMOLOGY;

DRUG DESIGN; HUMANS; LIGANDS; MOLECULAR DOCKING SIMULATION; PROTEIN BINDING; RECEPTORS, ESTROGEN; RECEPTORS, G-PROTEIN-COUPLED; SMALL MOLECULE LIBRARIES;

EID: 84871314506     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986712804485755     Document Type: Review

References (83)

1. Overington, J. P.; Al-Lazikani, B.; Hopkins, A. L. How many drug targets are there? Nat Rev Drug Discov., 2006, 5, 993-996.
2. Bockaert, J.; Pin, J. P. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J., 1999, 18, 1723-1729.
3. Rosenbaum, D. M.; Rasmussen, S. G.; Kobilka, B. K. The structure and function of G-protein-coupled receptors. Nature., 2009, 459, 356-63.
4. Lappano, R.; Maggiolini, M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov., 2011, 10, 47-60.
5. Filardo, E. J.; Quinn, J. A.; Bland, K. I.; Frackelton, A. R. Jr. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol, 2000, 10, 1649-60.
6. Revankar, CM.; Cimino, D. F.; Sklar, L. A.; Arterburn, J. B.; Prossnitz, E. R. A transmembrane intracellular estrogen receptor mediates rapid cell signalling. Science, 2005, 307, 1625-30.
7. Maggiolini, M.; Vivacqua, A.; Fasanella, G.; Recchia, A. G.; Sisci, D.; Pezzi, V.; Montanaro, D.; Musti, A. M.; Picard, D.; Andò, S. The G protein-coupled receptor GPR30 mediates c-fos upregulation by 17h-estradiol and phytoestrogens in breast cancer cells. J Biol Chem., 2004, 279, 27008-16.
8. Bologa, C. G.; Revankar, CM.; Young, S. M.; Edwards, B. S.; Arterburn, J. B.; Kiselyov, A. S.; Parker, M. A.; Tkachenko, S. E.; Savchuck, N. P.; Sklar, L. A.; Oprea, T. I.; Prossnitz, E. R. Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol, 2006;4:207-12.
9. Thomas, P.; Pang, Y.; Filardo, E. J.; Dong, J. Identity of an estrogen membrane receptor coupled to a G protein human breast cancer cells. Endocrinology, 2005, 146, 624-32.
10. Vivacqua, A.; Bonofiglio, D.; Recchia, A. G.; Musti, A. M.; Picard, D.; Andò, S.; Maggiolini, M. The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17β-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol Endocrinol, 2006, 20, 631-46.
11. Vivacqua, A.; Bonofiglio, D.; Albanito, L.; Madeo, A.; Rago, V.; Carpino, A.; Musti, A. M.; Picard, D.; Andò, S.; Maggiolini, M. 17h-Estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the G protein coupled-receptor GPR30. Mol Pharmacol, 2006b, 70, 1414-23.
12. Vivacqua, A.; Lappano, R.; De Marco, P.; Sisci, D.; Aquila, S.; De Amicis, F.; Fuqua, S. A.; Andò, S.; Maggiolini, M. G protein-coupled receptor 30 expression is up-regulated by EGF and TGF a in estrogen receptor alphapositive cancer cells. Mol Endocrinol, 2009, 23, 1815-1826.
13. Albanito, L.; Madeo, A.; Lappano, R.; Vivacqua, A.; Rago, V.; Carpino, A.; Oprea, T. I.; Prossnitz, E. R.; Musti, A. M.; Andò, S.; Maggiolini, M. G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17beta-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res, 2007, 67, 1859-66.
14. Prossnitz, E. R.; Maggiolini, M. Mechanisms of estrogen signaling and gene expression via GPR30. Mol Cell Endocrin., 2009, 308, 32-38.
15. Maggiolini, M.; Picard D. The unfolding stories of GPR30, a new membrane bound estrogen receptor. J Endocrinol, 2010, 204, 105-14.
16. Lappano, R.; Rosano, C.; De Marco P.; De Francesco E. M.; Pezzi V.; Maggiolini M. Estriol acts as a GPR30 antagonist in estrogen receptor-negative breast cancer cells. Mol Cell Endocrinol, 2010, 320, 162-70.
17. Lappano, R.; Rosano, C.; Santolla, M. F.; Pupo, M.; De Francesco, E. M.; De Marco, P.; Ponassi, M.; Spallarossa, A.; Ranise, A.; Maggiolini, M. Two novel GPER agonists induce gene expression changes and growth effects in cancer cells. Curr Cancer Drug Targets., 2012, 12, 531-42.
18. Lappano, R.; Santolla, M. F.; Pupo, M.; Sinicropi, M. S.; Caruso, A.; Rosano, C.; Maggiolini, M. MIBE acts as antagonist ligand of both estrogen receptor a and GPER in breast cancer cells. Breast Cancer Res., 2012, 14, R12.
19. Pandey, D. P.; Lappano, R.; Albanito, L.; Madeo, A.; Maggiolini, M.; Picard, D. Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J., 2009, 28, 523-32.
20. Madeo, A.; Maggiolini, M. Nuclear alternate estrogen receptor GPR30 mediates 17b-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts. Cancer Res., 2010, 70, 6036-6046.
21. Prossnitz, E. R.; Barton, M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol, 2011, 7, 715-26.
22. Filardo, E. J.; Graeber, C. T.; Quinn, J. A.; Resnick, M. B.; Giri, D.; DeLellis, R. A.; Steinhoff, M. M.; Sabo, E. Distribution of GPR30, a seven membranespanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin Cancer Res., 2006, 12, 6359-66.
23. Smith, H. O.; Leslie, K. K.; Singh, M. M.; Qualls, C. R.; Revankar, CM.; Joste, N. E.; Prossnitz, E. R. GPR30: a novel indicator of poor survival for endometrial carcinoma. Am J Obstet Gynecol, 2007, 196, 386.e1-386.e1 1.
24. Smith, H. O.; Arias-Pulido, H.; Kuo, D. Y.; Howard, T.; Qualls, C. R.; Lee, S. J.; Verschraegen, C. F.; Hathaway, H. J.; Joste, N. E.; Prossnitz, E. R. GPR30 predicts poor survival for ovarian cancer. Gynecol Oncol, 2009, 114, 465-71.
25. Albanito, L.; Sisci, D.; Aquila, S.; Brunelli, E.; Vivacqua, A.; Madeo, A.; Lappano, R.; Pandey, D. P.; Picard, D.; Mauro, L.; Andò, S.; Maggiolini, M. Epidermal growth factor induces G protein-coupled receptor 30 expression in estrogen receptor-negative breast cancer cells. Endocrinology, 2008, 149, 3799-3808.
26. De Marco, P.; Bartella, V.; Vivacqua, A.; Lappano, R.; Santolla, M. F.; Morcavallo, A.; Pezzi, V.; Belfiore, A.; Maggiolini M. (2012). Insulin-like growth factor-I regulates GPER expression and function in cancer cells. Oncogene., 2012 Mar. 19 [Epub ahead of print].
27. Deupi, X.; Kobilka, B. K. Activation of G Protein-Coupled Receptors. Adv Protein Chem. 2007, 74, 137-66.
28. Audet, M., Bouvier, M. Restructuring G Protein Coupled Receptor Activation. Cell, 2012, 151, 14-22
29. Jacob, L.; Hoffmann, B.; Stoven, V.; Vert, J. P. Virtual screening of GPCRs: an in silico chemogenomics approach. BMC Bioinformatics., 2008, 9, 363.
30. Henry, D. Intercalation mechanisms: antitumor drug design based upon helical DNA as a receptor site. Cancer Chemother Rep., 1972, 3, 50.
31. Balbi, A.; Anzaldi, M.; Macciò, C.; Aiello, C.; Mazzei, M.; Gangemi, R.; Castagnola, P.; Miele, M.; Rosano, C.; Viale, M. Synthesis and biological evaluation of novel pyrazole derivatives with anticancer activity Eur J Med Chem., 2011, 46, 5293-309.
32. Stec-Martyna, E.; Ponassi, M.; Miele, M.; Parodi, S.; Felli, L.; Rosano, C. Structural comparison of the interaction of tubulin with various ligands affecting microtubule dynamics. Curr Cancer Drug Targets., 2012, 12, 658-66.
33. Perdih, A.; Dolenc, M. S. Small molecule antagonists of integrin receptors. Curr Med Chem, 2010, 17, 2371-2392.
34. Claffey, M. M.; Helal, C. J.; Verhoest, P. R.; Kang, Z.; Bundesmann, M. W.; Hou, X.; Liu, S.; Kleiman, R. J.; Vanasse-Frawley, M.; Schmidt, A. W.; Menniti, F.; Schmidt, C. J.; Hoffman, W. E.; Hajos, M.; McDowell, L.; O'Connor, R. E.; Macdougal-Murphy, M.; Fonseca, K. R.; Becker, S. L.; Nelson, F. R.; Liras, S. Application of Structure-Based Drug Design and Parallel Chemistry to Identify Selective, Brain Penetrant, In Vivo Active Phosphodiesterase 9A Inhibitors. J Med Chem. 2012 Oct. 1. [Epub ahead of print]
35. Brvar, M.; Perdih, A.; Oblak, M.; Masic, L. P.; Solmajer, T. In silico discovery of 2-amino-4-(2, 4-dihydroxyphenyl) thiazoles as novel inhibitors of DNA gyrase B. Bioorg Med Chem Lett., 2010, 20, 958-62.
36. Shoichet, B. K.; Kobilca, B. K. Structure-based drug screening for G-proteincoupled receptors Trends Pharmacol Sci. 2012, 33, 268-72.
37. Kontoyianni, M.; Liu, Z. Structure-based design in the GPCR target space. Curr Med Chem, 2012, 19, 544-556.
38. Rosano, C. Molecular model of hexokinase binding to the outer mitochondrial membrane porin (VDAC1): Implication for the design of new cancer therapies. Mitochondrion., 2011, 11, 513-9.
39. Clothia, C.; Lesk, A. M. The relation between the divergence of sequence and structure in proteins. EMBO J, 1986, 5, 823-826.
40. Palczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C. A.; Motoshima, H.; Fox, B. A.; Le Trong, I.; Teller, D. C.; Okada, T.; Stenkamp, R. E.; Yamamoto, M.; Miyano, M. Crystal structure of rhodopsin: A G protein-coupled receptor. Science, 2000, 289, 739-45.
41. Rasmussen, S. G.; Choi, H. J.; Rosenbaum, D. M.; Kobilka, T. S.; Thian, F. S.; Edwards, P. C.; Burghammer, M.; Ratnala, V. R.; Sanishvili, R.; Fischetti, R. F.; Schertler, G. F.; Weis, W. I.; Kobilka, B. K. Crystal structure of the human p2adrenergic G-protein-coupled receptor. Nature, 2007, 450, 383-387.
42. Kim, D. E.; Chivian, D.; Baker, D. Protein structure prediction and analysis using the Robetta server. Nucleic Acids Res., 2004, 32 Suppl 2:W526-31.
43. Sali, A.; Blundell, T. L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol Biol, 1993, 234, 779-815.
44. Yohannan, S.; Faham, S.; Yang, D.; Whitelegge, J. P.; Bowie, J. U. The evolution of transmembrane helix kinks and the structural diversity of G protein-coupled receptors. Proc Natl Acad Sci U S A., 2004, 101, 959-63.
45. Rocchia, W.; Alexov, E.; Honig, B. Extending the Applicability of the Nonlinear Poisson-Boltzmann Equation: Multiple Dielectric Constants and Multivalent Ions. J. Phys. Chem. B, 2001, 105, 6507-6514.
46. Kuhn, P.; Wilson, K.; Patch, M. G.; Stevens, R. C. The genesis of highthroughput structure-based drug discovery using protein crystallography. Curr Opin Chem Biol, 2002, 6, 704-710.
47. Hardy, L. W.; Malikayil A. The impact of structure-guided drug design on clinical agents. Curr Drug Discov., 2003, 15-20.
48. Blundell, T. L.; Patel, S. High-throughput X-ray crystallography for drug discovery. Curr Opin Pharmacol, 2004, 4, 490-496.
49. Kryshtafovych, A.; Moult, J.; Bartual, S. G.; Bazan, J. F.; Berman, H.; Casteel, D. E.; Christodoulou, E.; Everett, J. K.; Hausmann, J.; Heidebrecht, T.; Hills, T.; Hui, R.; Hunt, J. F.; Seetharaman, J.; Joachimiak, A.; Kennedy, M. A.; Kim, C.; Lingel, A.; Michalska, K.; Montelione, G. T.; Otero, J. M.; Perrakis, A.; Pizarro, J. C.; van Raaij, M. J.; Ramelot, T. A.; Rousseau, F.; Tong, L.; Wernimont, A. K.; Young, J.; Schwede, T. Target highlights in CASP9: Experimental target structures for the critical assessment of techniques for protein structure prediction. Proteins., 2011, 79 Suppl 10, 6-20.
50. Sleator, R. D. Prediction of protein functions. Methods Mol Biol, 2012, 815, 15-24.
51. Michino, M.; Abola, E. GPCR Dock 2008 participants, Brooks, C. L. 3rd, Dixon, J. S., Moult, J., Stevens, R. C. Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008. Nat Rev Drug Discov., 2009, 8, 455-63.
52. Liu, T.; Tang, G. W.; Capriotti, E. Comparative modeling: the state of the art and protein drug target structure prediction. Comb Chem High Throughput Screen., 2011, 14, 532-47.
53. Albanito, L.; Lappano, R.; Madeo, A.; Chimento, A.; Prossnitz, E. R.; Cappello, A. R.; Dolce, V.; Abonante, S.; Pezzi, V.; Maggiolini, M. G-proteincoupled receptor 30 and estrogen receptor-alpha are involved in the proliferative effects induced by atrazine in ovarian cancer cells. Environ Health Perspect, 2008, 116, 1648-55.
54. Dennis, M. K.; Burai, R, Ramesh, C.; Petrie, W. K.; Alcon, S. N.; Nayak, T. K.; Bologa, C. G.; Leitao, A.; Brailoiu, E.; Deliu, E.; Dun, N. J.; Sklar, LA.; Hathaway, H. J.; Arterburn, J. B.; Oprea, T. I.; Prossnitz, E. R. In vivo effects of a GPR30 antagonist. Nat Chem Biol, 2009, 5, 421-7.
55. Lin, B. C.; Suzawa, M.; Blind, R. D.; Tobias, S. C.; Bulun, S. E.; Scanlan, T. S.; Ingraham, HA. Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation. Cancer Res., 2009, 69, 5415-23.
56. Kang, K.; Lee, S. B.; Jung, S. H.; Cha, K. H.; Park, W. D.; Sohn, Y. C.; Nho, C. W. Tectoridin, a poor ligand of estrogen receptor alpha, exerts its estrogenic effects via an ERK-dependent pathway. Mol Cells., 2009, 27, 351-7.
57. Ramesh, C.; Nayak, T. K.; Burai, R.; Dennis, M. K.; Hathaway, H. J.; Sklar, LA.; Prossnitz, E. R.; Arterburn, J. B. Synthesis and characterization of iodinated tetrahydroquinolines targeting the G protein-coupled estrogen receptor GPR30. J Med Chem., 2010, 53, 1004-14.
58. Dennis, M. K.; Field, A. S.; Burai, R.; Ramesh, C.; Petrie, W. K.; Bologa, C. G.; Oprea, T. I.; Yamaguchi, Y.; Hayashi, S.; Sklar, LA.; Hathaway, H. J.; Arterburn, J. B.; Prossnitz, E. R. Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity. J Steroid Biochem Mol Biol, 2011, 127, 358-66.
59. Hall, J. M.; Couse, J. F.; Korach, K. S. The multifaceted mechanisms of estradiol and estrogen receptor signalling. J. Biol. Chem 2001, 276:36869-72.
60. Rosano, C.; Stec-Martyna, E.; Lappano, R.; Maggiolini, M. Structure-based approach for the discovery of novel selective estrogen receptor modulators. Curr Med Chem., 2011, 18, 1188-94.
61. Ascenzi, P.; Bocedi, A.; Marino, M. Structure-function relationship of estrogen receptor alpha and beta: Impact on human health. Mol Aspects Med, 2006, 27, 299-402.
62. Barton, M. Position paper: The membrane estrogen receptor GPER/GPR30: Clues and questions. Steroids, 2012, 77, 935-42.
63. Thomas, P.; Dong, J. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption. Journal of Steroid Biochemistry and Molecular Biology, 2006, 102, 175-179.
64. Pupo, M.; Pisano, A.; Lappano, R.; Santolla M. F.; De Francesco F. M.; Rosano, C.; Maggiolini, M. Bisphenol A induces gene expression changes and proliferative effects through GPER in breast cancer cells and cancer-associated fibroblasts. Environ Health Perspect, 2012 May 2. [Epub ahead of print].
65. Shiau, A. K.; Barstad, D.; Loria, P. M.; Cheng, L.; Kushner, P. J.; Agard, DA.; Greene, G. L: The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell, 1998, 95, 927-937.
66. Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr D, 2004, D60, 2126-2132.
67. Morris, G. M.; Huey, R.; Olson, A. J. Using AutoDock for ligand-receptor docking. Curr Protoc Bioinformatics. 2008, Chapter 8:Unit 8. 14.
68. Jones, G.; Willett, P.; Glen, R. C. J. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation Mol. Biol, 1995, 245, 43-53.
69. Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem., 2004, 25, 1605-12.
70. Kuntz, ID.; Blaney, J. M.; Oatley, S. J.; Langridge, R.; Ferrin, T. E. A geometric approach to macromolecule-ligand interactions. J Mol Biol, 1982, 161, 269-88.
71. Kuhlbrant, W.; Gouaux, E. Membrane proteins. Curr. Opin. Struct. Biol, 1999, 9, 445-447.
72. Archer, E.; Maigret, B.; Escrieut, C.; Pradayrol, L.; Fourmy, D. Rhodopsin crystal: new template yielding realistic models of G-protein-coupled receptors? Trends Pharmacol Sci., 2003, 24, 36-40.
73. 1-adrenergic G-protein-coupled receptor. Nature, 2008, 454, 486-491.
74. Jaakola, V. P.; Griffith, M. T.; Hanson, M. A.; Cherezov, V.; Chien, E. Y.; Lane, J. R.; Ijzerman, A. P.; Stevens, R. C. The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science., 2008, 322, 1211-7.
75. Wu, B.; Chien, E. Y.; Mol, C. D.; Fenalti, G.; Liu, W.; Katritch, V.; Abagyan, R.; Brooun, A.; Wells, P.; Bi, F. C.; Hamel, D. J.; Kuhn, P.; Handel, T. M.; Cherezov, V.; Stevens, R. C. Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists. Science, 2010, 330, 1066-1071.
76. Chien E. Y.; Liu W.; Zhao Q.; Katritch V.; Han G. W.; Hanson M. A.; Shi L.; Newman A. H.; Javitch J. A.; Cherezov V.; Stevens R. C. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science, 2010, 330, 1091-1095.
77. Shimamura, T.; Shiroishi, M.; Weyand, S.; Tsujimoto, H.; Winter, G.; Katritch, V.; Abagyan, R.; Cherezov, V.; Liu, W.; Han, G. W.; Kobayashi, T.; Stevens, R. C.; Iwata, S. Structure of the human histamine H1 receptor complex with doxepin. Nature, 2011, 475, 65-70.
78. Hanson, M. A.; Roth, C. B.; Jo, E.; Griffith, M. T.; Scott, F. L.; Reinhart, G.; Desale, H.; Clemons, B.; Cahalan, S. M.; Schuerer, S. C.; Sanna, M. G.; Han, G. W.; Kuhn, P.; Rosen, H.; Stevens, R. C. Crystal structure of a lipid G protein-coupled receptor. Science., 2012, 335, 851-5.
79. Haga, K.; Kruse, A. C.; Asada, H.; Yurugi-Kobayashi, T.; Shiroishi, M.; Zhang, C.; Weis, W. I.; Okada, T.; Kobilka, B. K.; Haga, T.; Kobayashi, T. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature, 2012, 482, 547-551.
80. Granier, S.; Manglik, A.; Kruse, A. C.; Kobilka, T. S.; Thian, F. S.; Weis, W. I.; Kobilka, B. K. Structure of the δ-opioid receptor bound to naltrindole. Nature. 2012, 485, 400-4.
81. Wu, H.; Wacker, D.; Mileni, M.; Katritch, V.; Han, G. W.; Vardy, E.; Liu, W.; Thompson, A. A.; Huang, X. P.; Carroll, F. I.; Mascarella, S. W.; Westkaemper, R. B.; Mosier, P. D.; Roth, B. L.; Cherezov, V.; Stevens, R. C. Structure of the human κ-opioid receptor in complex with JDTic. Nature, 2012 Mar. 21. [E-pub ahead of print].
82. Manglik, A.; Kruse, A. C.; Kobilka, T. S.; Thian, F. S.; Mathiesen, J. M.; Sunahara, R. K.; Pardo, L.; Weis, W. I.; Kobilka, B. K.; Granier, S. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature, 2012 Mar. 21. [E-pub ahead of print].
83. Thompson, A. A.; Liu, W.; Chun, E.; Katritch, V.; Wu, H.; Vardy, E.; Huang, X. P.; Trapella, C.; Guerrini, R.; Calo, G.; Roth, B. L.; Cherezov, V.; Stevens, R. C. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature. 2012, 485, 395-9.