Skip to main content
SpringerLink
Log in

Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

  • Original Article
  • Published:
Bioscience Reports

Abstract

One of the largest family of cell surface proteins, G-protein coupled receptors (GPCRs) regulate virtually all known physiological processes in mammals. With seven transmembrane segments, they respond to diverse range of extracellular stimuli and represent a major class of drug targets. Peptidergic GPCRs use endogenous peptides as ligands. To understand the mechanism of GPCR activation and rational drug design, knowledge of three-dimensional structure of receptor–ligand complex is important. The endogenous peptide hormones are often short, flexible and completely disordered in aqueous solution. According to “Membrane Compartments Theory”, the flexible peptide binds to the membrane in the first step before it recognizes its receptor and the membrane-induced conformation is postulated to bind to the receptor in the second step. Structures of several peptide hormones have been determined in membrane-mimetic medium. In these studies, micelles, reverse micelles and bicelles have been used to mimic the cell membrane environment. Recently, conformations of two peptide hormones have also been studied in receptor-bound form. Membrane environment induces stable secondary structures in flexible peptide ligands and membrane-induced peptide structures have been correlated with their bioactivity. Results of site-directed mutagenesis, spectroscopy and other experimental studies along with the conformations determined in membrane medium have been used to interpret the role of individual residues in the peptide ligand. Structural differences of membrane-bound peptides that belong to the same family but differ in selectivity are likely to explain the mechanism of receptor selectivity and specificity of the ligands. Knowledge of peptide 3D structures in membrane environment has potential applications in rational drug design.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

Aib:

Alpha-aminoisobutyric acid

aPP:

Avian pancreatic polypeptide

bPP:

Bovine pancreatic polypeptide

CCK:

Cholecystokinin

CD:

Circular Dichroism

CNS:

Central nervous system

DCPC:

Dicaproylphosphatidylcholine

DHPC:

Dihexanoylphosphatidylcholine

DMPC:

Dimyristoylphosphatidylcholine

DMPG:

Dimyristoyl phosphoglycerol

DMSO:

Dimethyl sulfoxide

DOP-R:

δ opioid receptor

DPC:

Dodecylphosphocholine

DynA:

Dynorphin A

FTIR:

Fourier transform infrared

GPCR:

G Protein-coupled receptor

GRP:

Gastrin-releasing peptide

GRP-R:

GRP receptor

HFA:

Hexafluoroacetone

Hyp:

Hydroxyproline

IR-ATR spectroscopy:

Infrared-attenuated total reflection spectroscopy

KOP-R:

κ opioid receptor

Lenk:

Leucine-enkephalin

LMPC:

Lyso-myristoylphosphatidylcholine

MD:

Molecular dynamics

Menk:

Methionine-enkephalin

MOP-R:

μ opioid receptor

NKA:

Neurokinin A

NKB:

Neurokinin B

NMB:

Neuromedin B

NMB-R:

NMB receptor

NOE:

Nuclear overhauser effect

NOP-R:

Nociceptin/orphanin FQ receptor

NPγ:

Neuropeptide γ

NPAF:

Neuropeptide AF

NPFF:

Neuropeptide FF

NPK:

Neuropeptide K

NPY:

Neuropeptide Y

NT:

Neurotensin

NTR:

Neurotensin receptor

PACAP:

Pituitary adenylate cyclase-activating polypeptide

PDB:

Protein Data Bank

PP:

Pancreatic polypeptide

PYY:

Peptide YY

SDS:

Sodium dodecylsulfate

SP:

Substance P

TFE:

Trifluoroethanol

TM:

Transmembrane

TRNOE:

Transferred NOE

VIP:

Vasoactive intestinal peptide

VR:

Vasopressin receptor

References

  1. Wise A, Jupe SC, Rees S (2004) The identification of ligands at orphan G-protein coupled receptors. Annu Rev Pharmacol Toxicol 44:43–66

    PubMed  CAS  Google Scholar 

  2. Mertens I, Vandingenen A, Meeusen T, De Loof A, Schoofs L (2004) Postgenomic characterization of G-protein-coupled receptors. Pharmacogenomics 5:657–672

    PubMed  CAS  Google Scholar 

  3. Spiegel AM, Weinstein LS (2004) Inherited diseases involving G proteins and G protein-coupled receptors. Annu Rev Med 55:27–39

    PubMed  CAS  Google Scholar 

  4. Pierce KL, Premont RT, Lefkowitz RJ (2002) Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3:639–650

    PubMed  CAS  Google Scholar 

  5. Palczewski K, et al (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289:739–745

    PubMed  CAS  Google Scholar 

  6. Lu Z-L, Saldanha JW, Hulme EC (2002) Seven-transmembrane receptors: crystals clarify. Trends Pharmacol Sci 23:140–146

    PubMed  CAS  Google Scholar 

  7. Archer E, Maigret B, Escrieut C, Pradayrol L, Fourmy D, (2003) Rhodopsin crystal: new template yielding realistic models of G-protein-coupled receptors? Trends Pharmacol Sci 24:36–40

    PubMed  CAS  Google Scholar 

  8. Bywater RP (2005) Location and nature of the residues important for ligand recognition in G-protein coupled receptors. J Mol Recog 18:60–72

    CAS  Google Scholar 

  9. Becker OM, et al (2004) G protein-coupled receptors: in silico drug discovery in 3D. Proc Natl Acad Sci USA 101:11304–11309

    PubMed  CAS  Google Scholar 

  10. Becker OM, Shacham S, Marantz Y., Noiman S (2003) Modeling the 3D structure of GPCRs: advances and application to drug discovery. Curr Opin Drug Dis Dev 6:353–361

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  12. Blundell TL, Pitts JE, Tickle IJ, Wood SP, Wu C-W (1981) X-ray analysis (1.4 A resoultion) of avian pancreatic polypeptide: small globular protein hormone. Proc Natl Acad Sci USA 78:4175–4179

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  14. Deschamps JR, George C, Flippen-Anderson JL (1996) Structural studies of opioid peptides: a review of recent progress in X-ray diffraction studies. Biopolymers 40:121–139

    PubMed  CAS  Google Scholar 

  15. Kaiser ET, Kezdy FJ (1983) Secondary structures of proteins and peptides in amphiphilic environments (A review). Proc Natl Acad Sci USA 80:1137–1143

    PubMed  CAS  Google Scholar 

  16. Minakata H, Taylor JW, Walker MW, Miller RJ, Kaiser ET (1989) Characterization of amphiphilic secondary structures in neuropeptide Y through the design, synthesis and study of model peptides. J Biol Chem 264:7907–7913

    PubMed  CAS  Google Scholar 

  17. McLean LR, Buck SH, Krstenansky JL (1990) Examination of the role of the amphipathic alpha-helix in the interaction of neuropeptide Y and active cyclic analogues with cell membrane receptors and dimyristoylphosphatidylcholine. Biochemistry 29:2016–2022

    PubMed  CAS  Google Scholar 

  18. Schwyzer R (1991) Peptide-membrane interactions and a new principle in quantitative structure–activity relationships. Biopolymers 31:785–792

    PubMed  CAS  Google Scholar 

  19. Schwyzer R (1995) 100 years lock-and-key concept: are peptide keys shaped and guided to their receptors by the target cell membrane? Biopolymers (Peptide Science) 37:5–16

    CAS  Google Scholar 

  20. Moroder L, et al (1993) New evidence for a membrane-bound pathway in hormone receptor binding. Biochemistry 32:13551–13559

    PubMed  CAS  Google Scholar 

  21. Lancaster CRD, et al (1991) Mimicking the membrane-mediated conformation of dynorphin A-(1–13)-peptide: circular Dichroism and nuclear magnetic resonance studies in methanolic solution. Biochemistry 30:4715–4726

    PubMed  CAS  Google Scholar 

  22. Lee S, Kim Y (1999) Solution structure of neuromedin B by 1H nuclear magnetic resonance spectroscopy. FEBS Lett 460:263–269

    PubMed  CAS  Google Scholar 

  23. Miskolzie M, Kotovych G (2003) The NMR-derived conformation of neuropeptide AF, an orphan G-protein coupled receptor peptide. Biopolymers 69:201–215

    PubMed  CAS  Google Scholar 

  24. Saviano G, Crescenzi O, Picone D, Temussi PA, Tancredi T (1999) Solution structure of human beta-endorphin in helicogenic solvents: an NMR study. J Pept Sci 5:410–422

    PubMed  CAS  Google Scholar 

  25. Amodeo P, et al (2002) Solution structure of nociceptin peptides. J Pept Sci 8:497–509

    PubMed  CAS  Google Scholar 

  26. Damberg P, Jarvet J, Graslund A (2001) Micellar systems as solvents in peptide and protein structure determination. Methods Enzymol 339:271–285

    PubMed  CAS  Google Scholar 

  27. Bader R, Lerch M, Zerbe O (2002) NMR of membrane-associated peptides and proteins. In: Zerbe O (ed) BioNMR in drug research. Wiley-VCH, Weinheim, pp 95–117

    Google Scholar 

  28. Sanders CR, Hoffmann AK, Gray DN, Keyes MH, Ellis CD (2004) French swimwear for membrane proteins. ChemBioChem 5:423–426

    PubMed  CAS  Google Scholar 

  29. Henry HD, Sykes BD (1994) Methods to study membrane protein structure in solution. Methods Enzymol 239:515–535

    PubMed  CAS  Google Scholar 

  30. Lauterwein J, Bosch C, Brown LR, Wuthrich K (1979) Physicochemical studies of the protein–lipid interactions in melittin-containing micelles. Biochim Biophys Acta 556:244–264

    PubMed  CAS  Google Scholar 

  31. Opella SJ (1997) NMR and membrane proteins. Nature Struct Biol 4(Suppl):845–848

    CAS  PubMed  Google Scholar 

  32. Tamm LK, Abildgaard F, Arora A, Blad H, Bushweller JH (2003) Structure, dynamics and function of the outer membrane protein A (OmpA) and influenza hemagglutinin fusion domain in detergent micelles by solution NMR. FEBS Lett 555:139–143

    PubMed  CAS  Google Scholar 

  33. Inooka H, et al (2001) Conformation of a peptide ligand bound to its G-protein coupled receptor. Nature: Struct Biol 8:161–165

    CAS  Google Scholar 

  34. Fiori S, Renner C, Cramer J, Pegoraro S, Moroder L (1999) Preferred conformation of endomorphin-1 in aqueous and membrane-mimetic environments. J Mol Biol 291:163–175

    PubMed  CAS  Google Scholar 

  35. Rudolph-Bohner S, Quarzago D, Czisch M, Ragnarsson U, Moroder L (1997) Conformational preferences of Leu-enkephalin in reverse micelles as membrane-mimicking environment. Biopolymers 41:591–606

    CAS  Google Scholar 

  36. Marcotte I, Separovic F, Auger M, Gagne SM (2004) A multidimensional 1H NMR investigation of the conformation of methionine-enkephalin in fast-tumbling bicelles. Biophys J 86:1587–1600

    PubMed  CAS  Google Scholar 

  37. Sanders CR, Prosser RS (1998) Bicelles: a model membrane for all seasons? Structure 6:1227–1234

    PubMed  CAS  Google Scholar 

  38. Glover KJ, et al (2001) Structural evaluation of phospholipid bicelles for solution-state studies of membrane-associated biomolecules. Biophys J 81:2163–2171

    PubMed  CAS  Google Scholar 

  39. Tyndall JDA, Pfeiffer B, Abbenante G, Fairlie DP (2005) Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure. Chem Rev 105:793–826

    PubMed  CAS  Google Scholar 

  40. Noble F, et al (1999) International union of pharmacology. XXI. Structure, distribution, and functions of cholecystokinin receptors. Pharmacol Rev 51:745–781

    PubMed  CAS  Google Scholar 

  41. Rehfeld JF, Solinge WW (1994) The tumor biology of gastrin and cholecystokinin. Adv Cancer Res 63:295–347

    Article  PubMed  CAS  Google Scholar 

  42. Wank SA (1998) G protein-coupled receptors in gastrointestinal physiology. I. CCK receptors: an exemplary family. Am J Physiol 274:G607–G613

    PubMed  CAS  Google Scholar 

  43. Silvente-Poirot S, Dufresne M, Vaysse N, Fourmy D (1993) The peripheral cholecystokinin receptors. Eur J Biochem 215:513–529

    PubMed  CAS  Google Scholar 

  44. Saito A, Sankaran H, Goldfine ID, Williams JA (1980) Cholecystokinin receptors in the brain: characterization and distribution. Science 208:1155–1156

    PubMed  CAS  Google Scholar 

  45. Pellegrini M, Mierke DF (1999) Molecular complex of cholecystokinin-8 and N-terminus of the cholecystokinin A receptor by NMR spectroscopy. Biochemistry 38:14775–14783

    PubMed  CAS  Google Scholar 

  46. Giragossian C, Stone S, Papini AM, Moroder L, Mierke DF (2002) Conformational and molecular modeling studies of sulfated cholecystokinin-15. Biochem Biophys Res Commn 293:1053–1059

    CAS  Google Scholar 

  47. Bader R, Bettio A, Beck-Sickinger A, Zerbe O (2001) Structure and dynamics of micelle-bound neuropeptide Y: comparison with unligated NPY and implications for receptor selection. J Mol Biol 305:307–329

    PubMed  CAS  Google Scholar 

  48. Bader R, Rytz G, Lerch M, Beck-Sickinger AG, Zerbe O (2002) Key motif to gain selectivity at the Neuropeptide Y5-receptor: structure and dynamics of micelle-bound[Ala31, Pro32]-NPY. Biochemistry 41:8031–8042

    PubMed  CAS  Google Scholar 

  49. Lerch M, et al (2002) Bovine pancreatic polypeptide (bPP) undergoes significant changes in conformation and dynamics upon binding to DPC micelles. J Mol Biol 322:1117–1133

    PubMed  CAS  Google Scholar 

  50. Lerch M, Mayrhofer M, Zerbe O (2004) Structural similarities of micelle-bound peptide YY (PYY) and neuropeptide Y (NPY) are related to their affinity profiles at the Y receptors. J Mol Biol 339:1153–1168

    PubMed  CAS  Google Scholar 

  51. Tessmer MR, Kallick DA (1997) NMR and structural model of dynorphin A(1–17) bound to dodecylphosphocholine micelles. Biochemistry 36:1971–1981

    PubMed  CAS  Google Scholar 

  52. Miskolzie M, Lucyk S, Kotovych G (2003) NMR conformational studies of micelle-bound orexin-B: a neuropeptide involved in the sleep/awake cycle and feeding regulation. J Biomol Struct Dyn 21:341–351

    PubMed  CAS  Google Scholar 

  53. Grace RCR, Chandrashekar IR, Cowsik SM (2003) Solution structure of the tachykinin peptide eledoisin. Biophys J 84:665–664

    Google Scholar 

  54. Grace RCR, Lynn AM, Cowsik SM (2001) Lipid induced conformation of the tachykinin peptide kassinin. J Biomol Struct Dyn 18:611–625

    PubMed  CAS  Google Scholar 

  55. Keire DA, Fletcher TG (1996) The conformation of substance P in lipid environments. Biophys J 70:1716–1727

    PubMed  CAS  Google Scholar 

  56. Cowsik SM, Lucke C, Ruterjans H (1997) Lipid-induced conformation of substance P. J Biomol Struct Dyn 15:27–36

    PubMed  CAS  Google Scholar 

  57. Chandrashekar IR, Cowsik SM (2003) Three-dimensional structure of the mammalian tachykinin peptide neurokinin A bound to lipid micelles. Biophys J 85:4002–4011

    PubMed  CAS  Google Scholar 

  58. Whitehead TL, McNair SD, Hadden CE, Young JK, Hicks RP (1998) Membrane-induced secondary structures of neuropeptides: a comparison of the solution conformations adopted by agonists and antagonists of the mammalian tachykinin NK1 receptor. Biochemistry 41:1497–1506

    CAS  Google Scholar 

  59. Mantha AK, Chandrashekar IR, Baquer NZ, Cowsik SM (2004) Three dimensional structure of mammalian tachykinin peptide neurokinin B bound to lipid micelles. J Biomol Struct Dyn 22:137–147

    PubMed  CAS  Google Scholar 

  60. Chandrashekar IR, Dike A, Cowsik SM (2004) Membrane-induced structure of the mammalian tachychinin neuropeptide gamma. J Struct Biol 148:315–325

    PubMed  CAS  Google Scholar 

  61. Luca S, et al (2003) The conformation of neurotension bound to its G protein-coupled receptor. Proc Natl Acad Sci USA 100:10706–10711

    PubMed  CAS  Google Scholar 

  62. Miskolzie M, Kotovych G (2003) The NMR derived conformation of Orexin-A: an orphan G-protein coupled receptor agonist involved in appetite regulation and sleep. J Biomol Struct Dyn 21:201–210

    PubMed  CAS  Google Scholar 

  63. Berman HM, et al (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242

    PubMed  CAS  Google Scholar 

  64. Giragossian C, Mierke DF (2001) Intermolecular interactions between cholecystokinin-8 and the third extracellular loop of the cholecystokinin A receptor. Biochemistry 40:3804–3809

    PubMed  CAS  Google Scholar 

  65. Kennedy K, et al (1997) Identification of two amino acids of the human cholecystokinin-A receptor that interact with the N-terminal moiety of cholecystokinin. J Biol Chem 272:2920–2926

    PubMed  CAS  Google Scholar 

  66. Gigoux V, et al (1999) Arginine 336 and asparagine 333 of the human cholecystokinin-A receptor binding site interact with the penultimate aspartic acid and the C-terminal amide of cholecystokinin. J Biol Chem 274:20457–20464

    PubMed  CAS  Google Scholar 

  67. Kopin AS, McBride EW, Quinn SM, Kolakowski LF Jr, Beinborn M (1995) The role of the cholecystokinin-B/gastrin receptor transmembrane domains in determining affinity for subtype-selective ligands. J Biol Chem 270:5019–5023

    PubMed  CAS  Google Scholar 

  68. Spindel ER (2003) Bombesin-like peptides. In: Henry HL, Norman AW (eds) Encyclopedia of hormones. Elsevier–Academic Press, pp 198–205

  69. Yamada K, Wada E, Santo-Yamada Y, Wada K (2002) Bombesin and its family of peptides: prospects for the treatment of obesity. Eur J Pharmacol 440:281–290

    PubMed  CAS  Google Scholar 

  70. Ohki-Hamazaki H (2000) Neuromedin B. Prog Neurobiol 62:297–312

    PubMed  CAS  Google Scholar 

  71. Preston SR, Miller GV, Primrose JN (1996) Bombesin-like peptides and cancer. Crit Rev Oncol/Hematol 23:225–238

    CAS  Google Scholar 

  72. Lin J-T, Coy DH, Mantey SA, Jensen RT (1995) Comparison of the peptide structural requirements for high affinity interaction with bombesin receptors. Eur J Pharmacol 294:55–69

    PubMed  CAS  Google Scholar 

  73. Krane IM, Naylor SL, Helin-Davis D, Chin WW, Spindel ER (1988) Molecular cloning of cDNAs encoding the human bombesin-like peptide neuromedin B. Chromosomal localization and comparison to cDNAs encoding its amphibian homolog ranatensin. J Biol Chem 263:13317–13323

    PubMed  CAS  Google Scholar 

  74. Sainz E, Akeson M, Mantey SA, Jensen RT, Battey JF (1998) Four amino acid residues are critical for high affinity binding of neuromedin B to the neuromedin B receptor. J Biol Chem 273:15927–15932

    PubMed  CAS  Google Scholar 

  75. Akeson M, Sainz E, Mantey SA, Jensen RT, Battey JF (1997) Identification of four amino acids in the gastrin-releasing peptide receptor that are required for high affinity agonist binding. J Biol Chem 272:17405–17409

    PubMed  CAS  Google Scholar 

  76. Tokita K, Hocart SJ, Coy DH, Jensen RT (2002) Molecular basis of the selectivity of gastrin-releasing peptide receptor for gastrin-releasing peptide. Mol Pharm 61:1435–1443

    CAS  Google Scholar 

  77. Carver JA (1987) The conformation of bombesin in solution as determined by two-dimensional 1H-NMR techniques. Eur J Biochem 168:193–199

    PubMed  CAS  Google Scholar 

  78. Erne D, Schwyzer R (1987) Membrane structure of bombesin studied by infrared spectroscopy. Prediction of membrane interactions of gastrin-releasing peptide, neuromedin B, and neuromedin C. Biochemistry 26:6316–6319

    PubMed  CAS  Google Scholar 

  79. Polverini E, Casadio R, Neyroz P, Masotti L (1998) Conformational changes of neuromedin B and delta sleep-inducing peptide induced by their interaction with lipid membranes as revealed by spectroscopic techniques and molecular dynamics simulation. Arch Biochem Biophys 349:225–235

    PubMed  CAS  Google Scholar 

  80. Panula P, Aarnisalo AA, Wasowicz K (1996) Neuropeptide FF a mammalian neuropeptide with multiple functions. Prog Neurobiol 48:461–487

    PubMed  CAS  Google Scholar 

  81. Roumy M, Zajac J-M (1998) Neuropeptide FF, pain and analgesia. Eur J Pharmacol 345:1–11

    PubMed  CAS  Google Scholar 

  82. Perry SJ, et al (1997) A human gene encoding morphine modulating peptides related to NPFF and FMRFamide. FEBS Lett 409:426–430

    PubMed  CAS  Google Scholar 

  83. Panula P, et al (1999) Neuropeptide FF and modulation of pain. Brain Res 848:191–196

    PubMed  CAS  Google Scholar 

  84. Vilim FS, et al (1999) Gene for pain modulatory neuropeptide NPFF: induction in spinal cord by noxious stimuli. Mol Pharm 55:804–811

    CAS  Google Scholar 

  85. Elshourbagy NA, et al (2000) Receptor for the pain modulatory neuropeptides FF and AF is an orphan G protein-coupled receptor. J Biol Chem 275:25965–25971

    PubMed  CAS  Google Scholar 

  86. Kotani M, et al (2001) Functional characterization of a human receptor for neuropeptide FF and related peptides. Br J Pharmacol 133:138–144

    PubMed  CAS  Google Scholar 

  87. Bonini JA, et al (2000) Identification and characterization of two G protein-coupled receptors for neuropeptide FF. J Biol Chem 275:39324–39331

    PubMed  CAS  Google Scholar 

  88. Larhammer D (1996) Evolution of neuropeptide Y, peptide YY and pancreatic polypeptide. Regul Pept 62:1–11

    Google Scholar 

  89. Ekblad E, Sundler F (2002) Distribution of pancreatic polypeptide and peptide YY. Peptides 23:251–261

    PubMed  CAS  Google Scholar 

  90. Conlon JM (2002) The origin and evolution of peptide YY (PYY) and pancreatic polypeptide (PP). Peptides 23:269–278

    PubMed  Google Scholar 

  91. Yannielli PC, Harrington ME (2001) Neuropeptide Y in the mammalian circadian system: effects on light-induced circadian responses. Peptides 22:547–556

    PubMed  CAS  Google Scholar 

  92. Dumont Y, Martel J-C, Fournier A, St-Pierre S, Quirion R (1992) Neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues. Prog Neurobiol 38:125–167

    PubMed  CAS  Google Scholar 

  93. Pedrazzini T, Pralong F, Grouzmann E (2003) Neuropeptide Y: the universal soldier. Cell Mol Life Sci 60:350–377

    PubMed  CAS  Google Scholar 

  94. Thorsell A, Heilig M (2002) Diverse functions of neuropeptide Y revealed using genetically modified animals. Neuropeptides 36:182–193

    PubMed  CAS  Google Scholar 

  95. Small CJ, Bloom SR (2004) Gut hormones and the control of appetitie. Trends Endocrinol Metabol 15:259–263

    CAS  Google Scholar 

  96. Tschenett A, et al (2003) Reduced anxiety and improved stress and coping capability in mice lacking NPY-Y2 receptors. Eur J Neurosci 18:143–148

    PubMed  Google Scholar 

  97. Blomqvist AG, Herzog H (1997) Y-receptor subtypes – How many more? Trends Neurosci 20:294–298

    PubMed  CAS  Google Scholar 

  98. Michel MC, et al (1998) XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY and pancreatic polypeptide receptors. Pharmacol Rev 50:143–150

    PubMed  CAS  Google Scholar 

  99. Li X, Sutcliffe MJ, Schwartz TW, Dobson CM (1992) Sequence-specific 1H NMR assignments and solution structure of bovine pancreatic polypeptide. Biochemistry 31:1245–1253

    PubMed  CAS  Google Scholar 

  100. Monks S, Karagianis G, Howlett G, Norton RS (1996) Solution structure of human neuropeptide Y. J Biomol NMR 8:379–390

    PubMed  CAS  Google Scholar 

  101. Cowley DJ, Hoflack JM, Pelton JT, Saudek V (1992) Structure of neuropeptide Y dimer in solution. Eur J Biochem 205:1099–1166

    PubMed  CAS  Google Scholar 

  102. Beck-Sickinger AG, Jung G (1995) Structure–activity relationships of neuropeptide Y analogues with respect to Y1 and Y2 receptors. Biopolymers 37:123–142

    PubMed  CAS  Google Scholar 

  103. Cabrele C, Wieland HA, Koglin N, Stidsen C, Beck-Sickinger AG (2002) Ala(31)-Aib(32): identification of the key motif for high affinity and selectivity of neuropeptide Y at the Y5-receptor. Biochemistry 41:8043–8049

    PubMed  CAS  Google Scholar 

  104. Killian JA, von Heijne G (2000) How proteins adapt to a membrane–water interface. Trends Biochem Sci 25:429–434

    PubMed  CAS  Google Scholar 

  105. Beck-Sickinger AG, et al (1994) Complete L-alanine scan of neuropeptide Y reveals ligands binding to Y1 and Y2 receptors with distinguished conformations. Eur J Biochem 225:947–958

    PubMed  CAS  Google Scholar 

  106. Carraway R, Leeman SE (1973) The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem 248:6854–6861

    PubMed  CAS  Google Scholar 

  107. Tyler-McMahon BM, Boules M, Richelson E (2000) Neurotensin: peptide for the next millennium. Regul Pept 93:125–136

    PubMed  CAS  Google Scholar 

  108. Nemeroff CB (1980) Neurotensin: perchance an endogenous neuroleptic? Biol Psychiatry 15:283–302

    PubMed  CAS  Google Scholar 

  109. Tanaka K, Masu M, Nakanishi S (1990) Structure and functional expression of the cloned rat neurotensin receptor. Neuron 6:847–854

    Google Scholar 

  110. Vita N, et al (1993) Cloning and expression of a complementary DNA encoding a high affinity human neurotensin receptor. FEBS Lett 317:139–142

    PubMed  CAS  Google Scholar 

  111. Chalon P, et al (1996) Molecular cloning of a levocabastine-senistive neurotensin binding site. FEBS Lett 386:91–94

    PubMed  CAS  Google Scholar 

  112. Goedert M (1989) Radioligand-binding assays for study of neurotensin receptors. Methods Enzymol 168:462–481

    Article  PubMed  CAS  Google Scholar 

  113. Nieto JL, Rico M, Santora J, Herranz J, Bermejo FJ (1986) Assignment and conformation of neurotensin in aqueous solution by 1H NMR. Int J Pept Prot Res 28:315–323

    Article  CAS  Google Scholar 

  114. Xu GY, Deber CM (1991) Conformations of neurotensin in solution and in membrane environments studied by 2-D NMR spectroscopy. Int J Pept Prot Res 37:528–535

    Article  CAS  Google Scholar 

  115. Brownstein MJ (1993) A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci USA 90:5391–5393

    PubMed  CAS  Google Scholar 

  116. Vaccarino AL, Olson GA, Olson RD, Kastin AJ (1999) Endogenous opiates: 1998. Peptides 20:1527–1574

    PubMed  CAS  Google Scholar 

  117. Fuxe K, et al (1988) The opioid peptide systems: their organization and role in volume transmission and neuroendocrine regulation. In: Illes P, Farsang C (eds) Regulatory role of opioid peptides. VCH Verlagsgesellschaft, Weinheim, Germany, pp 33–68

    Google Scholar 

  118. Janecka A, Fichna J, Janecki T (2004) Opioid receptors and their ligands. Curr Top Med Chem 4:1–17

    PubMed  CAS  Google Scholar 

  119. Waldhoer M, Bartlett SE, Whistler JL (2004) Opioid receptor. Annu Rev Biochem 73:953–990

    PubMed  CAS  Google Scholar 

  120. Hollt V (1983) Multiple endogenous opioid peptides. Trends Neurosci 6:24–26

    Google Scholar 

  121. Henderson G, McKnight AT (1997) The orphan opioid receptor and its endogenous ligand-nociceptin/orphanin FQ. Trends Pharmacol Sci 18:293–300

    PubMed  CAS  Google Scholar 

  122. Zadina JE, Hackler L, Ge LJ, Kastin AJ (1997) A potent and selective endogenous agonist for the mu-opiate receptor. Nature 386:499–502

    PubMed  CAS  Google Scholar 

  123. Spadaccini R, Temussi PA (2001) Natural peptide analgesics: the role of solution conformation. Cell Mol Life Sci 58:1–11

    Google Scholar 

  124. Naito A, Nishimura K (2004) Conformational analysis of opioid peptides in the solid states and the membrane environments. Curr Top Med Chem 4:135–145

    PubMed  CAS  Google Scholar 

  125. Terenius L (1993) Opiate receptors – the historical breakthrough in drug research. Biochem Soc Symp 59:13–25

    PubMed  CAS  Google Scholar 

  126. Gysin B, Schwyzer R (1983) Head group and structure specific interactions of enkephalins and dynorphin with liposomes: investigation by hydrophobic photolabeling. Arch Biochem Biophys 225:467–474

    PubMed  CAS  Google Scholar 

  127. Young JK, Graham WH, Beard DJ, Hicks RP (1992) The use of UV-visible spectroscopy for the determination of hydrophobic interactions between neuropeptides and membrane model systems. Biopolymers 32:1061–1064

    PubMed  CAS  Google Scholar 

  128. Deber CM, Benham BA (1984) Role of membrane lipids in peptide hormone function: binding of enkephalins to micelles. Proc Natl Acad Sci USA 81:61–65

    PubMed  CAS  Google Scholar 

  129. Milon A, Miyazawa T, Higashijima T (1990) Transferred nuclear overhauser effect analyses of membrane-bound enkephalin analogues by 1H nuclear magnetic resonance: correlation between activities and membrane-bound conformations. Biochemistry 29:65–75

    PubMed  CAS  Google Scholar 

  130. Marcotte I, Dufourc EJ, Ouellet M, Auger M (2003) Interaction of the neuropeptide Met-enkephalin with zwitterionic and negatively charged bicelles as viewed by 31P and 2H solid-state NMR. Biophys J 85:328–339

    PubMed  CAS  Google Scholar 

  131. Schwyzer R, Moutevelis-Minakakis P, Kimura S, Gremlich H-L (1997) Lipid-induced secondary structures and orientations of [Leu5]-enkephalin: helical and crystallographic double-bend conformers revealed by IRATR and molecular modeling. J Pept Sci 3:65–81

    PubMed  CAS  Google Scholar 

  132. Graham WH, Carter ESI, Hicks RP (1992) Conformational analysis of Met-enkephalin in both aqueous solution and in the presence of sodium dodecyl sulfate micelles using multidimensional NMR and molecular modeling. Biopolymers 32:1755–1764

    PubMed  CAS  Google Scholar 

  133. Surewicz WK, Mantsch HH (1988) Solution and membrane structure of enkephalins as studied by infrared spectroscopy. Biochem Biophys Res Commun 150:245–251

    PubMed  CAS  Google Scholar 

  134. Takeuchi H, Ohtsuka Y, Harada I (1992) Ultraviolet resonance raman study on the binding mode of enkephalin to phospholipid membrane. J Am Chem Soc 114:5321–5328

    CAS  Google Scholar 

  135. Benham BA, Deber CM (1984) Evidence for a folded conformation of methionine- and leucine-enkephalin in a membrane environment. J Biol Chem 259:14935–14940

    Google Scholar 

  136. Chavkin C, Goldstein A (1981) Specific receptor for the opioid peptide dynorphin: structure–activity relationships. Proc Natl Acad Sci USA 78:6543–6547

    PubMed  CAS  Google Scholar 

  137. Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science 215:413–415

    PubMed  CAS  Google Scholar 

  138. Goldstein A, Fischli W, Lowney LI, Hunkapiller M, Hood L (1981) Porcine pituitary dynorphin: complete amino acid sequence of the biologically active heptadecapeptide. Proc Natl Acad Sci USA 78:7219–7223

    PubMed  CAS  Google Scholar 

  139. Naqvi T, Haq W, Mathur KB (1998) Structure–activity relationship studies of Dynorphin A and related peptides. Peptides 19:1277–1292

    PubMed  CAS  Google Scholar 

  140. Renugopalakrishnan V, Rapaka RS, Huang S-G, Moore S, Hutson TB (1988) Dynorphin A(1–13) peptide NH groups are solvent exposed: FT-IR and 500 MHz 1H NMR spectroscopic evidence. Biochem Biophys Res Commun 151:1220–1225

    PubMed  CAS  Google Scholar 

  141. Surewicz WK, Mantsch HH (1989) The conformation of dynorphin A-(1–13) in aqueous solution as studied by fourier transform infrared spectroscopy. J Mol Struct 214:143–147

    CAS  Google Scholar 

  142. Erne D, Sargent DF, Schwyzer R (1985) Preferred conformation, orientation, and accumulation of dynorphin A-(1–13)-tridecapeptide on the surface of neutral lipid membranes. Biochemistry 24:4261–4263

    PubMed  CAS  Google Scholar 

  143. Tessmer MR, Kallick DA (1997) Role of tryptophan-14 in the interaction of dynorphin A(1–17) with micelles. J Pept Res 49:427–431

    Article  PubMed  CAS  Google Scholar 

  144. Sankararamakrishnan R, Weinstein H (2000) Molecular dynamics simulations predict a tilted orientation for the helical region of dynorphin A(1–17) in dimyristoylphosphatidylcholine bilayers. Biophys J 79:2331–2344

    PubMed  CAS  Google Scholar 

  145. Sankararamakrishnan R, Weinstein H (2002) Positioning and stabilization of dynorphin peptides in membrane bilayers: the mechanistic role of aromatic and basic residues revealed from comparative MD simulations. J Phys Chem B 106:209–218

    CAS  Google Scholar 

  146. Sankararamakrishnan R, Weinstein H (2004) Surface tension parameterization in molecular dynamics simulations of a phospholipid-bilayer membrane: calibration and effects. J Phys Chem B 108:11802–11811

    CAS  Google Scholar 

  147. Sakurai T, et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585

    PubMed  CAS  Google Scholar 

  148. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M (2001) To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 24:429–458

    PubMed  CAS  Google Scholar 

  149. Nambu T, et al (1999) Distribution of orexin neurons in the adult rat brain. Brain Res 827:243–260

    PubMed  CAS  Google Scholar 

  150. Peyron C, et al (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6:991–997

    PubMed  CAS  Google Scholar 

  151. Lee J-H, et al (1999) Solution structure of a new hypothalamic neuropeptide, human hypocretin-2/orexin-B. Eur J Biochem 266:831–839

    PubMed  CAS  Google Scholar 

  152. Darker JG, et al (2001) Structure–activity analysis of truncated orexin-A analogues at the orexin-1 receptor. Bioorg Med Chem Lett 11:737–740

    PubMed  CAS  Google Scholar 

  153. Ammoun S, et al (2003) Distinct recognition of OX1 and OX2 receptors by orexin peptides. J Pharmacol Exp Ther 305:507–514

    PubMed  CAS  Google Scholar 

  154. Sherwood NM, Krueckl SL, McRory JE (2000) The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocrine Rev 21:619–670

    CAS  Google Scholar 

  155. Vaudry D, et al (2000) Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev 52:269–324

    PubMed  CAS  Google Scholar 

  156. Laburthe M, Couvineau A, Marie JC (2002) VPAC receptors for VIP and PACAP. Receptors & Channels 8:137–153

    CAS  Google Scholar 

  157. Hoare SRJ (2005) Mechanisms of peptide and nonpeptide ligand binding to class B G-protein-coupled receptors. Drug Discovery Today 10:417–427

    PubMed  CAS  Google Scholar 

  158. Krishnadas A, Onyuksel H, Rubinstein I (2003) Interactions of VIP, secretin and PACAP(1–38) with phospholipids: a biological paradox revisited. Curr Pharm Des 9:1005–1012

    PubMed  CAS  Google Scholar 

  159. Gololobov G, et al (1998) Stabilization of vasoactive intestinal peptide by lipids. J Pharmacol Exp Ther 285:753–758

    PubMed  CAS  Google Scholar 

  160. Gandhi S, Rubinstein I, Tsueshita T, Onyuksel H (2002) Secretin self-assembles and interacts spontaneously with phospholipids in vitro. Peptides 23:201–204

    PubMed  CAS  Google Scholar 

  161. Severini C, Improta G, Falconieri-Erspamer G, Salvadori S, Erspamer V (2002) The tachykinin peptide family. Pharmacol Rev 54:285–322

    PubMed  CAS  Google Scholar 

  162. Erspamer V (1994) Bioactive secreations of the integument. In: Heatwole H, Barthalmus GT (eds) Amphibian biology. I. The integuments. Surrey Beatty & Sons, Chipping Norton, NSW, Australia, pp 178–350

    Google Scholar 

  163. Pennefather JN, et al (2004) Tachykinins and tachykinin receptors: a growing family. Life Sci 74:1445–1463

    PubMed  CAS  Google Scholar 

  164. Nakanishi S (1991) Mammalian tachykinin receptors. Annu Rev Neurosci 14:123–136

    PubMed  CAS  Google Scholar 

  165. Maggi CA (1995) The mammalian tachykinin receptors. Gen Pharmacol 26:911–944

    PubMed  CAS  Google Scholar 

  166. Severini C, et al (2000) Parallel bioassay of 39 tachykinins on 11 smooth muscle preparations. Structure and receptor selectivity/affinity relationship. Peptides 21:1587–1595

    PubMed  CAS  Google Scholar 

  167. Almeida TA, et al (2004) Tachykinins and tachykinin receptors: structure and activity relationships. Curr Med Chem 11:2045–2081

    PubMed  CAS  Google Scholar 

  168. Schwarzer C, et al (1996) Neuropeptides-immunoreactivity and their mRNA expression in kindling: functional implications for limbic epileptogenesis. Brain Res Rev 22:27–50

    CAS  PubMed  Google Scholar 

  169. Barker R, (1996) Tachykinins, neurotrophism and neurodegenerative diseases: a critical review on the possible role of tachykinins in the aetiology of CNS diseases. Rev Neurosci 7:187–214

    PubMed  CAS  Google Scholar 

  170. Nawa H, Kotani H, Nakanishi S (1984) Tissue-specific generation of two preprotachykinin mRNAs from one gene by alternative RNA splicing. Nature 312:729–734

    PubMed  CAS  Google Scholar 

  171. Carter MS, Krause JE (1990) Structure, expression, and some regulatory mechanisms of the rat preprotachykinin gene encoding substance P, neurokinin A, neuropeptide K, and neuropeptide gamma. J Neurosci 10:2203–2214

    PubMed  CAS  Google Scholar 

  172. Kotani H, Hoshimaru M, Nawa H, Nakanishi S (1986) Structure and gene organization of bovine neuromedin K precursor. Proc Natl Acad Sci USA 83:7074–7078

    PubMed  CAS  Google Scholar 

  173. Rodziewicz-Motowidio S, et al (2002) The conformational solution studies of neuropeptide gamma using CD and NMR spectroscopy. J Pept Sci 8:211–226

    CAS  Google Scholar 

  174. Lee K, Lee S, Park NG, Kim Y (2003) Structures of neuropeptide gamma from goldfish and mammalian neuropeptide gamma, as determined by H-1 NMR spectroscopy. J Pept Res 61:274–285

    PubMed  CAS  Google Scholar 

  175. Chassaing G, Convert O, Lavielle S (1986) Preferential conformation of substance P in solution. Eur J Biochem 154:77–85

    PubMed  CAS  Google Scholar 

  176. Sumner SC, et al (1990) Conformational analysis of the tachykinins in solution: substance P and physalaemin. J Biomol Struct Dyn 8:687–707

    PubMed  CAS  Google Scholar 

  177. Young JK, Anklin C, Hicks RP (1994) NMR and molecular modeling investigations of the neuropeptide substance P in the presence of 15 mM sodium dodecyl sulfate micelles. Biopolymers 34:1449–1462

    PubMed  CAS  Google Scholar 

  178. Auge S, Bersch B, Tropis M, Milon A (2000) Characterization of substance P-membrane interaction by transferred nuclear overhauser effect. Biopolymers 54:297–306

    PubMed  CAS  Google Scholar 

  179. Keire DA, Kobayashi M (1998) The orientation and dynamics of substance P in lipid environments. Protein Sci. 7:2438–2450

    PubMed  CAS  Google Scholar 

  180. Bradshaw JP, Davies SMA, Hauss T (1998) Interaction of substance P with phospholipid bilayers: a neutron diffraction study. Biophys J 75:889–895

    PubMed  CAS  Google Scholar 

  181. Darkes MJM, Hauss T, Dante S, Bradshaw JP (2000) Revealing the membrane-bound structure of neurokinin A using neutron diffraction. Physica B 276–278:505–507

    Google Scholar 

  182. Tian C, et al (2005) Solution NMR spectroscopy of the human vasopressin V2 receptor, a G protein-coupled receptor. J Am Chem Soc 127:8010–8011

    PubMed  CAS  Google Scholar 

  183. White SH, Wimley WC (1999) Membrane protein folding and stability: physical principles. Annu Rev Biophys Biomol Struct 28:319–365

    PubMed  CAS  Google Scholar 

  184. Ulmschneider MB, Sansom MSP (2001) Amino acid distributions in integral membrane protein structures. Biochim Biophys Acta 1512:1–14

    PubMed  CAS  Google Scholar 

  185. Colson A-O, Perlman JH, Smolyar A, Gershengorn MC, Osman R (1998) Static and dynamic roles of extracellular loops in G-protein-coupled receptors: a mechanism for sequential binding of thyrotropin-releasing hormone to its receptor. Biophys J 74:1087–1100

    Article  PubMed  CAS  Google Scholar 

  186. Mehler EL, Periole X, Hassan SA, Weinstein H (2002) Key issues in the computational simulation of GPCR function: representation of loop domains. J Comp Aided Mol Des 16:841–853

    CAS  Google Scholar 

  187. Sankararamakrishnan R, Konvicka K, Mehler EL, Weinstein H (2000) Solvation in simulated annealing and high-temperature molecular dynamics of proteins: a restrained water droplet model. Int J Quant Chem 77:174–186

    CAS  Google Scholar 

Download references

Acknowledgements

I would like to thank all members of my lab for discussions. Priyanka Prakash Srivastava is acknowledged for her help while writing this review. This research is supported by Council of Scientific and Industrial Research (No. 37(1199)/04/EMR-II).

Author information

Authors and Affiliations

  1. Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, 208 016, India

    Ramasubbu Sankararamakrishnan

Authors
  1. Ramasubbu Sankararamakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramasubbu Sankararamakrishnan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sankararamakrishnan, R. Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment. Biosci Rep 26, 131–158 (2006). https://doi.org/10.1007/s10540-006-9014-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10540-006-9014-z

Keywords

Search

Navigation