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01.03.2018 | Review Article

Current understanding of the structure and function of family B GPCRs to design novel drugs

verfasst von: Vlasios Karageorgos, Maria Venihaki, Stelios Sakellaris, Michail Pardalos, George Kontakis, Minos-Timotheos Matsoukas, Achille Gravanis, Andreas Margioris, George Liapakis

Erschienen in: Hormones | Ausgabe 1/2018

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Abstract

Family B of G-protein-coupled receptors (GPCRs) and their ligands play a central role in a number of homeostatic mechanisms in the endocrine, gastrointestinal, skeletal, immune, cardiovascular and central nervous systems. Alterations in family B GPCR-regulated homeostatic mechanisms may cause a variety of potentially life-threatening conditions, signifying the necessity to develop novel ligands targeting these receptors. Obtaining structural and functional information on family B GPCRs will accelerate the development of novel drugs to target these receptors. Family B GPCRs are proteins that span the plasma membrane seven times, thus forming seven transmembrane domains (TM1-TM7) which are connected to each other by three extracellular (EL) and three intracellular (IL) loops. In addition, these receptors have a long extracellular N-domain and an intracellular C-tail. The upper parts of the TMs and ELs form the J-domain of receptors. The C-terminal region of peptides first binds to the N-domain of receptors. This ‘first-step’ interaction orients the N-terminal region of peptides towards the J-domain of receptors, thus resulting in a ‘second-step’ of ligand-receptor interaction that activates the receptor. Activation-associated structural changes of receptors are transmitted through TMs to their intracellular regions and are responsible for their interaction with the G proteins and activation of the latter, thus resulting in a biological effect. This review summarizes the current information regarding the structure and function of family B GPCRs and their physiological and pathophysiological roles.

Ishihara T, Nakamura S, Kaziro Y, Takahashi T, Takahashi K, Nagata S (1991) Molecular cloning and expression of a cDNA encoding the secretin receptor. EMBO J 10:1635–1641PubMedPubMedCentralCrossRef

Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63:1256–1272PubMedCrossRef

Alexander SP, Davenport AP, Kelly E et al (2015) The concise guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. Br J Pharmacol 172:5744–5869PubMedPubMedCentralCrossRef

Grammatopoulos DK, Chrousos GP (2002) Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends Endocrinol Metab 13:436–444PubMedCrossRef

Roh J, Chang CL, Bhalla A, Klein C, Hsu SY (2004) Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J Biol Chem 279:7264–7274PubMedCrossRef

Russell FA, King R, Smillie SJ, Kodji X, Brain SD (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 94:1099–1142PubMedPubMedCentralCrossRef

Poyner DR, Sexton PM, Marshall I et al (2002) International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev 54:233–246PubMedCrossRef

Hay DL, Christopoulos G, Christopoulos A, Poyner DR, Sexton PM (2005) Pharmacological discrimination of calcitonin receptor: receptor activity-modifying protein complexes. Mol Pharmacol 67:1655–1665PubMedCrossRef

Sexton PM, Albiston A, Morfis M, Tilakaratne N (2001) Receptor activity modifying proteins. Cell Signal 13:73–83PubMedCrossRef

10.

Gingell JJ, Simms J, Barwell J et al (2016) An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology. Cell Discov 2:16020PubMedPubMedCentralCrossRef

11.

Wootten D, Lindmark H, Kadmiel M et al (2013) Receptor activity modifying proteins (RAMPs) interact with the VPAC2 receptor and CRF1 receptors and modulate their function. Br J Pharmacol 168:822–834PubMedPubMedCentralCrossRef

12.

Christopoulos A, Christopoulos G, Morfis M et al (2003) Novel receptor partners and function of receptor activity-modifying proteins. J Biol Chem 278:3293–3297PubMedCrossRef

13.

Degn KB, Juhl CB, Sturis J et al (2004) One week's treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 53:1187–1194PubMedCrossRef

14.

Agerso H, Jensen LB, Elbrond B, Rolan P, Zdravkovic M (2002) The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 45:195–202PubMedCrossRef

15.

Berkovic MC, Bilic-Curcic I, Herman Mahecic D, Gradiser M, Grgurevic M, Bozek T (2017) Long-term effectiveness of Liraglutide in association with Patients' baseline characteristics in real-life setting in Croatia: an observational, retrospective, multicenter study. Diabetes Ther 8:1297–1308PubMedPubMedCentralCrossRef

16.

Hiramatsu T, Ozeki A, Ishikawa H, Furuta S (2017) Long term effects of Liraglutide in Japanese patients with type 2 diabetes among the subgroups with different renal functions: results of 2-year prospective study. Drug Res(Stuttg) 67:640–646

17.

Marso SP, Daniels GH, Brown-Frandsen K et al (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375:311–322PubMedPubMedCentralCrossRef

18.

JFE M, Orsted DD, Brown-Frandsen K et al LEADER Steering Committee Investigators 2017 Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med 377:839–848

19.

Riddle M, Frias J, Zhang B et al (2007) Pramlintide improved glycemic control and reduced weight in patients with type 2 diabetes using basal insulin. Diabetes Care 30:2794–2799PubMedCrossRef

20.

Riddle M, Pencek R, Charenkavanich S, Lutz K, Wilhelm K, Porter L (2009) Randomized comparison of pramlintide or mealtime insulin added to basal insulin treatment for patients with type 2 diabetes. Diabetes Care 32:1577–1582PubMedPubMedCentralCrossRef

21.

Monnier L (2007) Is pramlintide a safe and effective adjunct therapy for patients with type 1 diabetes? Nat Clin Pract Endocrinol Metab 3:332–333PubMedCrossRef

22.

Grunfeld C, Dritselis A, Kirkpatrick P (2011) Tesamorelin. Nat Rev Drug Discov 10:95–96PubMedCrossRef

23.

Miller PD, Bilezikian JP, Deal C, Harris ST, Ci RP (2004) Clinical use of teriparatide in the real world: initial insights. Endocr Pract 10:139–148PubMedCrossRef

24.

Orwoll ES, Shapiro J, Veith S et al (2014) Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J Clin Invest 124:491–498PubMedPubMedCentralCrossRef

25.

Kraenzlin ME, Meier C (2011) Parathyroid hormone analogues in the treatment of osteoporosis. Nat Rev Endocrinol 7:647–656PubMedCrossRef

26.

Shirley M (2017) Abaloparatide: First Global Approval. Drugs 77:1363–1368PubMedCrossRef

27.

Leder BZ, O'Dea LS, Zanchetta JR et al (2015) Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 100:697–706PubMedCrossRef

28.

Yoh K, Uzawa T, Orito T, Tanaka K (2012) Improvement of quality of life (QOL) in osteoporotic patients by Elcatonin treatment: a trial taking the Participants' preference into account. Jpn Clin Med 3:9–14PubMedPubMedCentralCrossRef

29.

Brunton L, Parker K, Blumenthal D, Buxton I. Goodman and Gilman's. Manual of Pharmacology and Therapeutics. The McGraw-Hill Companies, Inc.

30.

Jeppesen PB (2006) Glucagon-like peptide-2: update of the recent clinical trials. Gastroenterology 130(Suppl 1):27–131

31.

Jeppesen PB, Sanguinetti EL, Buchman A et al (2005) Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut 54:1224–1231PubMedPubMedCentralCrossRef

32.

Marier JF, Beliveau M, Mouksassi MS et al (2008) Pharmacokinetics, safety, and tolerability of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, following multiple ascending subcutaneous administrations in healthy subjects. J Clin Pharmacol 48:1289–1299PubMedCrossRef

33.

Goadsby PJ, Reuter U, Hallstrom Y et al (2017) A controlled trial of Erenumab for episodic migraine. N Engl J Med 377:2123–2132PubMedCrossRef

34.

Schuster NM, Rapoport AM (2017) Calcitonin gene-related peptide-targeted therapies for migraine and cluster headache: a review. Clin Neuropharmacol 40:169–174PubMedCrossRef

35.

Zorrilla EP, Koob GF (2010) Progress in corticotropin-releasing factor-1 antagonist development. Drug Discov Today 15:371–383PubMedPubMedCentralCrossRef

36.

Zorrilla EP, Heilig M, de Wit H, Shaham Y (2013) Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism. Drug Alcohol Depend 128:175–186PubMedPubMedCentralCrossRef

37.

2004 Corticorelin: ACTH RF, corticoliberin, corticotrophin-releasing hormone, corticotropin-releasing factor, human corticotropin-releasing hormone, ovine corticotrophin-releasing factor, Xerecept. Drugs RD 5: 218–219

38.

Recht L, Mechtler LL, Wong ET, O'Connor PC, Rodda BE (2013) Steroid-sparing effect of corticorelin acetate in peritumoral cerebral edema is associated with improvement in steroid-induced myopathy. J Clin Oncol 31:1182–1187PubMedCrossRef

39.

Kornreich WD, Galyean R, Hernandez JF et al (1992) Alanine series of ovine corticotropin releasing factor (oCRF): a structure-activity relationship study. J Med Chem 35:1870–1876PubMedCrossRef

40.

Nicole P, Lins L, Rouyer-Fessard C et al (2000) Identification of key residues for interaction of vasoactive intestinal peptide with human VPAC1 and VPAC2 receptors and development of a highly selective VPAC1 receptor agonist. Alanine scanning and molecular modeling of the peptide. J Biol Chem 275:24003–24012PubMedCrossRef

41.

Igarashi H, Ito T, Hou W et al (2002) Elucidation of vasoactive intestinal peptide pharmacophore for VPAC(1) receptors in human, rat, and Guinea pig. J Pharmacol Exp Ther 301:37–50PubMedCrossRef

42.

Bourgault S, Vaudry D, Segalas-Milazzo I et al (2009) Molecular and conformational determinants of pituitary adenylate cyclase-activating polypeptide (PACAP) for activation of the PAC1 receptor. J Med Chem 52:3308–3316PubMedCrossRef

43.

Adelhorst K, Hedegaard BB, Knudsen LB, Kirk O (1994) Structure-activity studies of glucagon-like peptide-1. J Biol Chem 269:6275–6278PubMed

44.

Dong M, Le A, Te JA, Pinon DI, Bordner AJ, Miller LJ (2011) Importance of each residue within secretin for receptor binding and biological activity. Biochemistry 50:2983–2993PubMedPubMedCentralCrossRef

45.

Watkins HA, Au M, Bobby R et al (2013) Identification of key residues involved in adrenomedullin binding to the AM1 receptor. Br J Pharmacol 169:143–155PubMedPubMedCentralCrossRef

46.

Bourgault S, Vaudry D, Guilhaudis L et al (2008) Biological and structural analysis of truncated analogs of PACAP27. J Mol Neurosci 36:260–269PubMedCrossRef

47.

Vale W, Spiess J, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394–1397PubMedCrossRef

48.

Ohta N, Mochizuki T, Hoshino M, Jun L, Kobayashi H, Yanaihara N (1997) Adrenocorticotropic hormone-releasing activity of urotensin I and its fragments in vitro. J Pept Res 50:178–183PubMedCrossRef

49.

Rivier J, Rivier C, Vale W (1984) Synthetic competitive antagonists of corticotropin-releasing factor: effect on ACTH secretion in the rat. Science 224:889–891PubMedCrossRef

50.

Turner JT, Jones SB, Bylund DB (1986) A fragment of vasoactive intestinal peptide, VIP(10-28), is an antagonist of VIP in the colon carcinoma cell line, HT29. Peptides 7:849–854PubMedCrossRef

51.

Goke R, Fehmann HC, Linn T et al (1993) Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem 268:19650–19655PubMed

52.

Pozvek G, Hilton JM, Quiza M, Houssami S, Sexton PM (1997) Structure/function relationships of calcitonin analogues as agonists, antagonists, or inverse agonists in a constitutively activated receptor cell system. Mol Pharmacol 51:658–665PubMedCrossRef

53.

Montrose-Rafizadeh C, Yang H, Rodgers BD, Beday A, Pritchette LA, Eng J (1997) High potency antagonists of the pancreatic glucagon-like peptide-1 receptor. J Biol Chem 272:21201–21206PubMedCrossRef

54.

Runge S, Thogersen H, Madsen K, Lau J, Rudolph R (2008) Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain. J Biol Chem 283:11340–11347PubMedCrossRef

55.

Underwood CR, Garibay P, Knudsen LB et al (2010) Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor. J Biol Chem 285:723–730PubMedCrossRef

56.

Parthier C, Kleinschmidt M, Neumann P et al (2007) Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor. Proc Natl Acad Sci U S A 104:13942–13947PubMedPubMedCentralCrossRef

57.

Sun C, Song D, Davis-Taber RA et al (2007) Solution structure and mutational analysis of pituitary adenylate cyclase-activating polypeptide binding to the extracellular domain of PAC1-RS. Proc Natl Acad Sci U S A 104:7875–7880PubMedPubMedCentralCrossRef

58.

Pioszak AA, Xu HE (2008) Molecular recognition of parathyroid hormone by its G protein-coupled receptor. Proc Natl Acad Sci U S A 105:5034–5039PubMedPubMedCentralCrossRef

59.

Grace CR, Perrin MH, Gulyas J et al (2007) Structure of the N-terminal domain of a type B1 G protein-coupled receptor in complex with a peptide ligand. Proc Natl Acad Sci U S A 104:4858–4863PubMedPubMedCentralCrossRef

60.

Inooka H, Ohtaki T, Kitahara O et al (2001) Conformation of a peptide ligand bound to its G-protein coupled receptor. Nat Struct Biol 8:161–165PubMedCrossRef

61.

Pallai PV, Mabilia M, Goodman M, Vale W, Rivier J (1983) Structural homology of corticotropin-releasing factor, sauvagine, and urotensin I: circular dichroism and prediction studies. Proc Natl Acad Sci U S A 80:6770–6774PubMedPubMedCentralCrossRef

62.

Dathe M, Fabian H, Gast K et al (1996) Conformational differences of ovine and human corticotropin releasing hormone. A CD, IR, NMR and dynamic light scattering study. Int J Pept Protein Res 47:383–393PubMedCrossRef

63.

Lau SH, Rivier J, Vale W, Kaiser ET, Kezdy FJ (1983) Surface properties of an amphiphilic peptide hormone and of its analog: corticotropin-releasing factor and sauvagine. Proc Natl Acad Sci U S A 80:7070–7074PubMedPubMedCentralCrossRef

64.

Neidigh JW, Fesinmeyer RM, Prickett KS, Andersen NH (2001) Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states. Biochemistry 40:13188–13200PubMedCrossRef

65.

Chang X, Keller D, Bjørn S, Led JJ (2001) Structure and folding of glucagon-like peptide-1-(7–36)-amide in aqueous trifluoroethanol studied by NMR spectroscopy. Magn Reson Chem 39:477–483CrossRef

66.

Fry DC, Madison VS, Bolin DR, Greeley DN, Toome V, Wegrzynski BB (1989) Solution structure of an analogue of vasoactive intestinal peptide as determined by two-dimensional NMR and circular dichroism spectroscopies and constrained molecular dynamics. Biochemistry 28:2399–2409PubMedCrossRef

67.

Gronenborn AM, Bovermann G, Clore GM (1987) A 1H-NMR study of the solution conformation of secretin. Resonance assignment and secondary structure. FEBS Lett 215:88–94PubMedCrossRef

68.

Braun W, Wider G, Lee KH, Wuthrich K (1983) Conformation of glucagon in a lipid-water interphase by 1H nuclear magnetic resonance. J Mol Biol 169:921–948PubMedCrossRef

69.

Wray V, Kakoschke C, Nokihara K, Naruse S (1993) Solution structure of pituitary adenylate cyclase activating polypeptide by nuclear magnetic resonance spectroscopy. Biochemistry 32:5832–5841PubMedCrossRef

70.

Sasaki K, Dockerill S, Adamiak DA, Tickle IJ, Blundell T (1975) X-ray analysis of glucagon and its relationship to receptor binding. Nature 257:751–757PubMedCrossRef

71.

Motta A, Andreotti G, Amodeo P, Strazzullo G, Castiglione Morelli MA (1998) Solution structure of human calcitonin in membrane-mimetic environment: the role of the amphipathic helix. Proteins 32:314–323PubMedCrossRef

72.

Thornton K, Gorenstein DG (1994) Structure of glucagon-like peptide (7-36) amide in a dodecylphosphocholine micelle as determined by 2D NMR. Biochemistry 33:3532–3539PubMedCrossRef

73.

O'Neil KT, DeGrado WF (1990) A thermodynamic scale for the helix-forming tendencies of the commonly occurring amino acids. Science 250:646–651PubMedCrossRef

74.

Beyermann M, Rothemund S, Heinrich N et al (2000) A role for a helical connector between two receptor binding sites of a long-chain peptide hormone. J Biol Chem 275:5702–5709PubMedCrossRef

75.

Stroop SD, Kuestner RE, Serwold TF, Chen L, Moore EE (1995) Chimeric human calcitonin and glucagon receptors reveal two dissociable calcitonin interaction sites. Biochemistry 34:1050–1057PubMedCrossRef

76.

Lopez de Maturana R, Willshaw A, Kuntzsch A, Rudolph R, Donnelly D (2003) The isolated N-terminal domain of the glucagon-like peptide-1 (GLP-1) receptor binds exendin peptides with much higher affinity than GLP-1. J Biol Chem 278:10195–10200PubMedCrossRef

77.

Pioszak AA, Parker NR, Suino-Powell K, Xu HE (2008) Molecular recognition of corticotropin-releasing factor by its G-protein-coupled receptor CRFR1. J Biol Chem 283:32900–32912PubMedPubMedCentralCrossRef

78.

Pal K, Swaminathan K, Xu HE, Pioszak AA (2010) Structural basis for hormone recognition by the human CRFR2{alpha} G protein-coupled receptor. J Biol Chem 285:40351–40361PubMedPubMedCentralCrossRef

79.

Harikumar KG, Lam PC, Dong M, Sexton PM, Abagyan R, Miller LJ (2007) Fluorescence resonance energy transfer analysis of secretin docking to its receptor: mapping distances between residues distributed throughout the ligand pharmacophore and distinct receptor residues. J Biol Chem 282:32834–32843PubMedCrossRef

80.

Perrin MH, Sutton S, Bain DL, Berggren WT, Vale WW (1998) The first extracellular domain of corticotropin releasing factor-R1 contains major binding determinants for urocortin and astressin. Endocrinology 139:566–570PubMedCrossRef

81.

Klose J, Fechner K, Beyermann M et al (2005) Impact of N-terminal domains for corticotropin-releasing factor (CRF) receptor-ligand interactions. Biochemistry 44:1614–1623PubMedCrossRef

82.

Mesleh MF, Shirley WA, Heise CE, Ling N, Maki RA, Laura RP (2007) NMR structural characterization of a minimal peptide antagonist bound to the extracellular domain of the corticotropin-releasing factor1 receptor. J Biol Chem 282:6338–6346PubMedCrossRef

83.

Runge S, Wulff BS, Madsen K, Brauner-Osborne H, Knudsen LB (2003) Different domains of the glucagon and glucagon-like peptide-1 receptors provide the critical determinants of ligand selectivity. Br J Pharmacol 138:787–794PubMedPubMedCentralCrossRef

84.

Dong M, Pinon DI, Cox RF, Miller LJ (2004) Importance of the amino terminus in secretin family G protein-coupled receptors. Intrinsic photoaffinity labeling establishes initial docking constraints for the calcitonin receptor. J Biol Chem 279:1167–1175PubMedCrossRef

85.

Gkountelias K, Tselios T, Venihaki M et al (2009) Alanine scanning mutagenesis of the second extracellular loop of type 1 corticotropin-releasing factor receptor revealed residues critical for peptide binding. Mol Pharmacol 75:793–800PubMedCrossRef

86.

Assil-Kishawi I, Abou-Samra AB (2002) Sauvagine cross-links to the second extracellular loop of the corticotropin-releasing factor type 1 receptor. J Biol Chem 277:32558–32561PubMedCrossRef

87.

Kraetke O, Holeran B, Berger H, Escher E, Bienert M, Beyermann M (2005) Photoaffinity cross-linking of the corticotropin-releasing factor receptor type 1 with photoreactive urocortin analogues. Biochemistry 44:15569–15577PubMedCrossRef

88.

Assil-Kishawi I, Samra TA, Mierke DF, Abou-Samra AB (2008) Residue 17 of sauvagine cross-links to the first transmembrane domain of corticotropin-releasing factor receptor 1 (CRFR1). J Biol Chem 283:35644–35651PubMedPubMedCentralCrossRef

89.

Coin I, Katritch V, Sun T et al (2013) Genetically encoded chemical probes in cells reveal the binding path of urocortin-I to CRF class B GPCR. Cell 155:1258–1269PubMedPubMedCentralCrossRef

90.

Bisello A, Adams AE, Mierke DF et al (1998) Parathyroid hormone-receptor interactions identified directly by photocross-linking and molecular modeling studies. J Biol Chem 273:22498–22505PubMedCrossRef

91.

Dong M, Li Z, Pinon DI, Lybrand TP, Miller LJ (2004) Spatial approximation between the amino terminus of a peptide agonist and the top of the sixth transmembrane segment of the secretin receptor. J Biol Chem 279:2894–2903PubMedCrossRef

92.

Dong M, Pinon DI, Cox RF, Miller LJ (2004) Molecular approximation between a residue in the amino-terminal region of calcitonin and the third extracellular loop of the class B G protein-coupled calcitonin receptor. J Biol Chem 279:31177–31182PubMedCrossRef

93.

Dong M, Xu X, Ball AM, Makhoul JA, Lam PC, Pinon DI, Orry A, Sexton PM, Abagyan R, Miller LJ (2012) Mapping spatial approximations between the amino terminus of secretin and each of the extracellular loops of its receptor using cysteine trapping. FASEB J 26:5092–5105PubMedPubMedCentralCrossRef

94.

Runge S, Gram C, Brauner-Osborne H, Madsen K, Knudsen LB, Wulff BS (2003) Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus. J Biol Chem 278:28005–28010PubMedCrossRef

95.

Al-Sabah S, Donnelly D (2003) The positive charge at Lys-288 of the glucagon-like peptide-1 (GLP-1) receptor is important for binding the N-terminus of peptide agonists. FEBS Lett 553:342–346PubMedCrossRef

96.

Di Paolo E, De Neef P, Moguilevsky N et al (1998) Contribution of the second transmembrane helix of the secretin receptor to the positioning of secretin. FEBS Lett 424:207–210PubMedCrossRef

97.

Bergwitz C, Gardella TJ, Flannery MR et al (1996) Full activation of chimeric receptors by hybrids between parathyroid hormone and calcitonin. Evidence for a common pattern of ligand-receptor interaction. J Biol Chem 271:26469–26472PubMedCrossRef

98.

Hoare SR, Fleck BA, Gross RS, Crowe PD, Williams JP, Grigoriadis DE (2008) Allosteric ligands for the corticotropin releasing factor type 1 receptor modulate conformational states involved in receptor activation. Mol Pharmacol 73:1371–1380PubMedCrossRef

99.

Hoare SR, Sullivan SK, Schwarz DA et al (2004) Ligand affinity for amino-terminal and juxtamembrane domains of the corticotropin releasing factor type I receptor: regulation by G-protein and nonpeptide antagonists. Biochemistry 43:3996–4011PubMedCrossRef

100.

Hoare SR, Gardella TJ, Usdin TB (2001) Evaluating the signal transduction mechanism of the parathyroid hormone 1 receptor. Effect of receptor-G-protein interaction on the ligand binding mechanism and receptor conformation. J Biol Chem 276:7741–7753PubMedCrossRef

101.

Nielsen SM, Nielsen LZ, Hjorth SA, Perrin MH, Vale WW (2000) Constitutive activation of tethered-peptide/corticotropin-releasing factor receptor chimeras. Proc Natl Acad Sci U S A 97:10277–10281PubMedPubMedCentralCrossRef

102.

Spyridaki K, Matsoukas MT, Cordomi A et al (2014) Structural-functional analysis of the third transmembrane domain of the corticotropin-releasing factor type 1 receptor: role in activation and allosteric antagonism. J Biol Chem 289:18966–18977PubMedPubMedCentralCrossRef

103.

Castro M, Nikolaev VO, Palm D, Lohse MJ, Vilardaga JP (2005) Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism. Proc Natl Acad Sci U S A 102:16084–16089PubMedPubMedCentralCrossRef

104.

Koth CM, Murray JM, Mukund S et al (2012) Molecular basis for negative regulation of the glucagon receptor. Proc Natl Acad Sci U S A 109:14393–14398PubMedPubMedCentralCrossRef

105.

Grace CR, Perrin MH, DiGruccio MR et al (2004) NMR structure and peptide hormone binding site of the first extracellular domain of a type B1 G protein-coupled receptor. Proc Natl Acad Sci U S A 101:12836–12841PubMedPubMedCentralCrossRef

106.

Grace CR, Perrin MH, Gulyas J et al (2010) NMR structure of the first extracellular domain of corticotropin-releasing factor receptor 1 (ECD1-CRF-R1) complexed with a high affinity agonist. J Biol Chem 285:38580–38589PubMedPubMedCentralCrossRef

107.

Pioszak AA, Parker NR, Gardella TJ, Xu HE (2009) Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides. J Biol Chem 284:28382–28391PubMedPubMedCentralCrossRef

108.

Perrin MH, Grace CR, Digruccio MR et al (2007) Distinct structural and functional roles of conserved residues in the first extracellular domain of receptors for corticotropin releasing factor and related G-protein coupled receptors. J Biol Chem 282:37529–37536PubMedCrossRef

109.

ter Haar E, Koth CM, Abdul-Manan N et al (2010) Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism. Structure 18:1083–1109PubMedCrossRef

110.

Norman DG, Barlow PN, Baron M, Day AJ, Sim RB, Campbell ID (1991) Three-dimensional structure of a complement control protein module in solution. J Mol Biol 219:717–725PubMedCrossRef

111.

Perrin MH, Grace CR, Riek R, Vale WW (2006) The three-dimensional structure of the N-terminal domain of corticotropin-releasing factor receptors: sushi domains and the B1 family of G protein-coupled receptors. Ann N Y Acad Sci 1070:105–119PubMedCrossRef

112.

Wilmen A, Goke B, Goke R (1996) The isolated N-terminal extracellular domain of the glucagon-like peptide-1 (GLP)-1 receptor has intrinsic binding activity. FEBS Lett 398:43–47PubMedCrossRef

113.

Gaudin P, Couvineau A, Maoret JJ, Rouyer-Fessard C, Laburthe M (1995) Mutational analysis of cysteine residues within the extracellular domains of the human vasoactive intestinal peptide (VIP) 1 receptor identifies seven mutants that are defective in VIP binding. Biochem Biophys Res Commun 211:901–908PubMedCrossRef

114.

Qi LJ, Leung AT, Xiong Y, Marx KA, Abou-Samra AB (1997) Extracellular cysteines of the corticotropin-releasing factor receptor are critical for ligand interaction. Biochemistry 36:12442–12448PubMedCrossRef

115.

Lin SC, Lin CR, Gukovsky I, Lusis AJ, Sawchenko PE, Rosenfeld MG (1993) Molecular basis of the little mouse phenotype and implications for cell type-specific growth. Nature 364:208–213PubMedCrossRef

116.

Parameswaran N, Spielman WS (2006) RAMPs: the past, present and future. Trends Biochem Sci 31:631–638PubMedCrossRef

117.

Hay DL, Pioszak AA (2016) Receptor activity-modifying proteins (RAMPs): new insights and roles. Annu Rev Pharmacol Toxicol 56:469–487PubMedCrossRef

118.

Weston C, Winfield I, Harris M et al (2016) Receptor activity-modifying protein-directed G protein signaling specificity for the calcitonin gene-related peptide family of receptors. J Biol Chem 291:21925–21944PubMedPubMedCentralCrossRef

119.

Archbold JK, Flanagan JU, Watkins HA, Gingell JJ, Hay DL (2011) Structural insights into RAMP modification of secretin family G protein-coupled receptors: implications for drug development. Trends Pharmacol Sci 32:591–600PubMedCrossRef

120.

de Graaf C, Song G, Cao C et al (2017) Extending the structural view of class B GPCRs. Trends Biochem Sci 42:946–960PubMedCrossRef

121.

Siu FY, He M, de Graaf C et al (2013) Structure of the human glucagon class B G-protein-coupled receptor. Nature 499:444–449PubMedCrossRef

122.

Jazayeri A, Dore AS, Lamb D et al (2016) Extra-helical binding site of a glucagon receptor antagonist. Nature 533:274–277PubMedCrossRef

123.

Hollenstein K, Kean J, Bortolato A et al (2013) Structure of class B GPCR corticotropin-releasing factor receptor 1. Nature 499:438–443PubMedCrossRef

124.

Song G, Yang D, Wang Y et al (2017) Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature 546:312–315PubMedCrossRef

125.

Zhang Y, Sun B, Feng D et al (2017) Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546:248–253PubMedPubMedCentralCrossRef

126.

Zhang H, Qiao A, Yang D et al (2017) Structure of the full-length glucagon class B G-protein-coupled receptor. Nature 546:259–264PubMedPubMedCentralCrossRef

127.

Liang YL, Khoshouei M, Radjainia M et al (2017) Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature 546:118–123PubMedPubMedCentralCrossRef

128.

Bortolato A, Dore AS, Hollenstein K, Tehan BG, Mason JS, Marshall FH (2014) Structure of class B GPCRs: new horizons for drug discovery. Br J Pharmacol 171:3132–3145PubMedPubMedCentralCrossRef

129.

Ballesteros J, Weinstein H (1995) Integrated methods for the construction of three-dimensional models of structure-function relations in G protein-coupled receptors. Methods in. Neurosciences 25:366–428CrossRef

130.

Wootten D, Simms J, Miller LJ, Christopoulos A, Sexton PM (2013) 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 110:5211–5216PubMedPubMedCentralCrossRef

131.

Rasmussen SG, DeVree BT, Zou Y et al (2011) Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477:549–555PubMedPubMedCentralCrossRef

132.

Rashid AJ, O'Dowd BF, George SR (2004) Minireview: diversity and complexity of signaling through peptidergic G protein-coupled receptors. Endocrinology 145:2645–2652PubMedCrossRef

133.

Hillhouse EW, Grammatopoulos DK (2006) The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev 27:260–286PubMedCrossRef

134.

Culhane KJ, Liu Y, Cai Y, Yan EC (2015) Transmembrane signal transduction by peptide hormones via family B G protein-coupled receptors. Front Pharmacol 6:264PubMedPubMedCentralCrossRef

135.

Punn A, Chen J, Delidaki M et al (2012) Mapping structural determinants within third intracellular loop that direct signaling specificity of type 1 corticotropin-releasing hormone receptor. J Biol Chem 287:8974–8985PubMedPubMedCentralCrossRef

136.

Conner AC, Simms J, Conner MT, Wootten DL, Wheatley M, Poyner DR (2006) Diverse functional motifs within the three intracellular loops of the CGRP1 receptor. Biochemistry 45:12976–12985PubMedCrossRef

137.

Huang Z, Chen Y, Pratt S et al (1996) The N-terminal region of the third intracellular loop of the parathyroid hormone (PTH)/PTH-related peptide receptor is critical for coupling to cAMP and inositol phosphate/Ca2+ signal transduction pathways. J Biol Chem 271:33382–33389PubMedCrossRef

138.

Hallbrink M, Holmqvist T, Olsson M, Ostenson CG, Efendic S, Langel U (2001) Different domains in the third intracellular loop of the GLP-1 receptor are responsible for Galpha(s) and Galpha(i)/Galpha(o) activation. Biochim Biophys Acta 1546:79–86PubMedCrossRef

139.

Chan KY, Pang RT, Chow BK (2001) Functional segregation of the highly conserved basic motifs within the third endoloop of the human secretin receptor. Endocrinology 142:3926–3934PubMedCrossRef

140.

Mathi SK, Chan Y, Li X, Wheeler MB (1997) Scanning of the glucagon-like peptide-1 receptor localizes G protein-activating determinants primarily to the N terminus of the third intracellular loop. Mol Endocrinol 11:424–432PubMedCrossRef

141.

Couvineau A, Lacapere JJ, Tan YV, Rouyer-Fessard C, Nicole P, Laburthe M (2003) Identification of cytoplasmic domains of hVPAC1 receptor required for activation of adenylyl cyclase. Crucial role of two charged amino acids strictly conserved in class II G protein-coupled receptors. J Biol Chem 278:24759–24766PubMedCrossRef

142.

Garcia GL, Dong M, Miller LJ (2012) Differential determinants for coupling of distinct G proteins with the class B secretin receptor. Am J Physiol Cell Physiol 302:C1202–C1212PubMedPubMedCentralCrossRef

143.

Bavec A, Hallbrink M, Langel U, Zorko M (2003) Different role of intracellular loops of glucagon-like peptide-1 receptor in G-protein coupling. Regul Pept 111:137–144PubMedCrossRef

144.

Cypess AM, Unson CG, Wu CR, Sakmar TP (1999) Two cytoplasmic loops of the glucagon receptor are required to elevate cAMP or intracellular calcium. J Biol Chem 274:19455–19464PubMedCrossRef

145.

Takhar S, Gyomorey S, Su RC, Mathi SK, Li X, Wheeler MB (1996) The third cytoplasmic domain of the GLP-1[7-36 amide] receptor is required for coupling to the adenylyl cyclase system. Endocrinology 137:2175–2178PubMedCrossRef

146.

Iida-Klein A, Guo J, Takemura M et al (1997) Mutations in the second cytoplasmic loop of the rat parathyroid hormone (PTH)/PTH-related protein receptor result in selective loss of PTH-stimulated phospholipase C activity. J Biol Chem 272:6882–6889PubMedCrossRef

147.

Ferrandon S, Feinstein TN, Castro M et al (2009) Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat Chem Biol 5:734–742PubMedPubMedCentralCrossRef

148.

Rasmussen SG, Choi H-J, Fung JJ et al (2011) Structure of a nanobody-stabilized active state of the [bgr] 2 adrenoceptor. Nature 469:175–180PubMedPubMedCentralCrossRef

149.

Chen YL, Obach RS, Braselton J et al (2008) 2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists. J Med Chem 51:1385–1392PubMedCrossRef

150.

Hoare SR, Brown BT, Santos MA, Malany S, Betz SF, Grigoriadis DE (2006) Single amino acid residue determinants of non-peptide antagonist binding to the corticotropin-releasing factor1 (CRF1) receptor. Biochem Pharmacol 72:244–255PubMedCrossRef

151.

Liaw CW, Grigoriadis DE, Lorang MT, De Souza EB, Maki RA (1997) Localization of agonist- and antagonist-binding domains of human corticotropin-releasing factor receptors. Mol Endocrinol 11:2048–2053PubMedCrossRef

152.

Sun X, Cheng J, Wang X, Tang Y, Agren H, Tu Y (2015) Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1. Sci Rep 5:8066PubMedPubMedCentralCrossRef

Titel: Current understanding of the structure and function of family B GPCRs to design novel drugs
verfasst von: Vlasios Karageorgos
Maria Venihaki
Stelios Sakellaris
Michail Pardalos
George Kontakis
Minos-Timotheos Matsoukas
Achille Gravanis
Andreas Margioris
George Liapakis
Publikationsdatum: 01.03.2018
Verlag: Springer International Publishing
Erschienen in: Hormones / Ausgabe 1/2018
Print ISSN: 1109-3099
Elektronische ISSN: 2520-8721
DOI: https://doi.org/10.1007/s42000-018-0009-5

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