Recent developments in biased agonism

Current Opinion in Cell Biology

Volumn 27, Issue 1, 2014, Pages 18-24

  Wisler, James W ^a   Xiao, Kunhong ^a   Thomsen, Alex RB ^a   Lefkowitz, Robert J ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANALGESIC AGENT; BETA 2 ADRENERGIC RECEPTOR; BETA ARRESTIN; CHEMOKINE RECEPTOR CCR5; CHOLECYSTOKININ B RECEPTOR; FUROSEMIDE; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR KINASE 2; G PROTEIN COUPLED RECEPTOR KINASE 3; G PROTEIN COUPLED RECEPTOR KINASE 6; GHRELIN RECEPTOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GUANINE NUCLEOTIDE BINDING PROTEIN; HORMONE RECEPTOR STIMULATING AGENT; LIGAND; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; MORPHINE; MUSCARINIC M2 RECEPTOR; RHODOPSIN; THROMBOXANE A2 RECEPTOR; TRV 120027; TRV 130; UNCLASSIFIED DRUG;

ANALGESIC ACTIVITY; CELL MATURATION; CONFORMATIONAL TRANSITION; DRUG ACTIVITY; DRUG SAFETY; DRUG TOLERABILITY; HUMAN; LIGAND BINDING; MOLECULAR MECHANICS; NONHUMAN; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; RECEPTOR BINDING; REVIEW; SIGNAL TRANSDUCTION; AGONISTS; ANIMAL; BIOPHYSICS; CHEMISTRY; METABOLISM;

ANIMALS; BIOPHYSICAL PHENOMENA; HUMANS; LIGANDS; PROTEIN CONFORMATION; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 84888056396     PISSN: 09550674     EISSN: 18790410     Source Type: Journal    
DOI: 10.1016/j.ceb.2013.10.008     Document Type: Review

References (64)

1. May L.T., et al. Allosteric modulation of G protein-coupled receptors. Ann Rev Pharmacol Toxicol 2007, 47:1-51.
2. Zidar D.A., et al. Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands. Proc Natl Acad Sci U S A 2009, 106:9649-9654.
3. Nobles K.N., et al. Distinct phosphorylation sites on the beta(2)-adrenergic receptor establish a barcode that encodes differential functions of beta-arrestin. Sci Signal 2011, 4:ra51.
4. Jones B.W., Hinkle P.M. Arrestin binds to different phosphorylated regions of the thyrotropin-releasing hormone receptor with distinct functional consequences. Mol Pharmacol 2008, 74:195-202.
5. Jones B.W., et al. Phosphorylation of the endogenous thyrotropin-releasing hormone receptor in pituitary GH3 cells and pituitary tissue revealed by phosphosite-specific antibodies. J Biol Chem 2007, 282:12893-12906.
6. Kim J., et al. Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling. Proc Natl Acad Sci U S A 2005, 102:1442-1447.
7. Ren X.R., et al. Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor. Proc Natl Acad Sci U S A 2005, 102:1448-1453.
8. Shenoy S.K., et al. Beta-arrestin-dependent: G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. J Biol Chem 2006, 281:1261-1273.
9. Kara E., et al. A phosphorylation cluster of five serine and threonine residues in the C-terminus of the follicle-stimulating hormone receptor is important for desensitization but not for beta-arrestin-mediated ERK activation. Mol Endocrinol 2006, 20:3014-3026.
10. Wisler J.W., et al. A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci U S A 2007, 104:16657-16662.
11. Blattermann S., et al. A biased ligand for OXE-R uncouples Galpha and Gbetagamma signaling within a heterotrimer. Nat Chem Biol 2012, 8:631-638.
12. Rasmussen S.G., et al. Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 2011, 477:549-555.
13. Bunemann M., Frank M., Lohse M.J. Gi protein activation in intact cells involves subunit rearrangement rather than dissociation. Proc Natl Acad Sci U S A 2003, 100:16077-16082.
14. Frank M., et al. G Protein activation without subunit dissociation depends on a G{alpha}(i)-specific region. J Biol Chem 2005, 280:24584-24590.
15. Kenakin T., Christopoulos A. Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat Rev Drug Discov 2013, 12:205-216.
16. Kenakin T., Christopoulos A. Measurements of ligand bias and functional affinity. Nat Rev Drug Discov 2013, 12:483.
17. Kenakin T., et al. A simple method for quantifying functional selectivity and agonist bias. ACS Chem Neurosci 2012, 3:193-203.
18. Rajagopal S., et al. Quantifying ligand bias at seven-transmembrane receptors. Mol Pharmacol 2011, 80:367-377.
19. Rajagopal S. Quantifying biased agonism: understanding the links between affinity and efficacy. Nat Rev Drug Discov 2013, 12:483.
20. Rajagopal S., Rajagopal K., Lefkowitz R.J. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 2010, 9:373-386.
21. Onaran H.O., Costa T. Where have all the active receptor states gone?. Nat Chem Biol 2012, 8:674-677.
22. Sauliere A., et al. Deciphering biased-agonism complexity reveals a new active AT1 receptor entity. Nat Chem Biol 2012, 8:622-630.
23. Busnelli M., et al. Functional selective oxytocin-derived agonists discriminate between individual G protein family subtypes. J Biol Chem 2012, 287:3617-3629.
24. Wei H., et al. Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proc Natl Acad Sci U S A 2003, 100:10782-10787.
25. Reversi A., et al. The oxytocin receptor antagonist atosiban inhibits cell growth via a biased agonist mechanism. J Biol Chem 2005, 280:16311-16318.
26. Kobilka B. The structural basis of G-protein-coupled receptor signaling (Nobel Lecture). Angew Chem Int Ed Engl 2013, 52:6380-6388.
27. Kahsai A.W., et al. Multiple ligand-specific conformations of the beta2-adrenergic receptor. Nat Chem Biol 2011, 7:692-700.
28. Deupi X., Kobilka B.K. Energy landscapes as a tool to integrate GPCR structure, dynamics, and function. Physiology (Bethesda) 2010, 25:293-303.
29. Yao X.J., et al. The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex. Proc Natl Acad Sci U S A 2009, 106:9501-9506.
30. Yao X., et al. Coupling ligand structure to specific conformational switches in the beta2-adrenoceptor. Nat Chem Biol 2006, 2:417-422.
31. 19F NMR. Science 2012, 335:1106-1110.
32. Altenbach C., et al. High-resolution distance mapping in rhodopsin reveals the pattern of helix movement due to activation. Proc Natl Acad Sci U S A 2008, 105:7439-7444.
33. West G.M., et al. Ligand-dependent perturbation of the conformational ensemble for the GPCR beta2 adrenergic receptor revealed by HDX. Structure 2011, 19:1424-1432.
34. Rahmeh R., et al. Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy. Proc Natl Acad Sci U S A 2012, 109:6733-6738.
35. Koole C., et al. Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) has a critical role in GLP-1 peptide binding and receptor activation. J Biol Chem 2012, 287:3642-3658.
36. Gregory K.J., et al. Stimulus bias provides evidence for conformational constraints in the structure of a G protein-coupled receptor. J Biol Chem 2012, 287:37066-37077.
37. Magnan R., et al. Distinct CCK-2 receptor conformations associated with beta-arrestin-2 recruitment or phospholipase-C activation revealed by a biased antagonist. J Am Chem Soc 2013, 135:2560-2573.
38. Steen A., et al. Biased and constitutive signaling in the CC-chemokine receptor CCR5 by manipulating the interface between transmembrane helices 6 and 7. J Biol Chem 2013, 288:12511-12521.
39. Nygaard R., et al. The dynamic process of beta(2)-adrenergic receptor activation. Cell 2013, 152:532-542.
40. Orban T., et al. Conformational dynamics of activation for the pentameric complex of dimeric G protein-coupled receptor and heterotrimeric G protein. Structure 2012, 20:826-840.
41. Mary S., et al. Ligands and signaling proteins govern the conformational landscape explored by a G protein-coupled receptor. Proc Natl Acad Sci U S A 2012, 109:8304-8309.
42. Frey A.J., et al. Biased suppression of TP homodimerization and signaling through disruption of a TM GxxxGxxxL helical interaction motif. J Lipid Res 2013, 54:1678-1690.
43. Abrol R., et al. Conformational ensemble view of G protein-coupled receptors and the effect of mutations and ligand binding. Methods Enzymol 2013, 520:31-48.
44. Abrol R., et al. Characterizing and predicting the functional and conformational diversity of seven-transmembrane proteins. Methods 2011, 55:405-414.
45. Kofuku Y., et al. Efficacy of the beta(2)-adrenergic receptor is determined by conformational equilibrium in the transmembrane region. Nat Commun 2012, 3:1045.
46. Lebon G., et al. Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation. Nature 2011, 474:521-525.
47. Xu F., et al. Structure of an agonist-bound human A2A adenosine receptor. Science 2011, 332:322-327.
48. Wacker D., et al. Structural features for functional selectivity at serotonin receptors. Science 2013, 340:615-619.
49. Warne T., et al. Crystal structures of a stabilized beta1-adrenoceptor bound to the biased agonists bucindolol and carvedilol. Structure 2012, 20:841-849.
50. Warne T., et al. The structural basis for agonist and partial agonist action on a beta(1)-adrenergic receptor. Nature 2011, 469:241-244.
51. Wang C., et al. Structural basis for molecular recognition at serotonin receptors. Science 2013, 340:610-614.
52. Hollenstein K., et al. Structure of class B GPCR corticotropin-releasing factor receptor 1. Nature 2013, 499:438-443.
53. Siu F.Y., et al. Structure of the human glucagon class B G-protein-coupled receptor. Nature 2013, 499:444-449.
54. Wootten D., et al. Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations. Proc Natl Acad Sci U S A 2013, 110:5211-5216.
55. Rajagopal K., et al. Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc Natl Acad Sci U S A 2006, 103:16284-16289.
56. Violin J.D., et al. Selectively engaging beta-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J Pharmacol Exp Therap 2010, 335:572-579.
57. Boerrigter G., et al. Cardiorenal actions of TRV120027, a novel beta-arrestin-biased ligand at the angiotensin II type I receptor, in healthy and heart failure canines: a novel therapeutic strategy for acute heart failure. Circ Heart Fail 2011, 4:770-778.
58. Monasky M.M., et al. The beta-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium. Amer J Physiol Heart Circ Physiol 2013.
59. Boerrigter G., et al. TRV120027: a novel beta-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure. Circ Heart Fail 2012, 5:627-634.
60. Soergel D.G., et al. First clinical experience with TRV027: pharmacokinetics and pharmacodynamics in healthy volunteers. J Clin Pharmacol 2013, 53:892-899.
61. Bohn L.M., et al. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 1999, 286:2495-2498.
62. Raehal K.M., Walker J.K., Bohn L.M. Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Therap 2005, 314:1195-1201.
63. DeWire S.M., et al. A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Therap 2013, 344:708-717.
64. Soergel D.G., et al. First human dosing experience with TRV130, a biased ligand at the Mu opioid receptor (P02.013). Neurology 2013, 80(Meeting Abstracts 1):P02.013.