In Vitro Mutagenesis Studies of Melanocortin Receptor Coupling and Ligand Binding

  • Carrie Haskell-Luevano
Part of the The Receptors book series (REC)


The melanocyte stimulating hormone receptor (MSH-R); melanocortin 1 receptor (MC1-R) and the adrenocorticotropin hormone (ACTH) receptor (MC2-R) were the first melanocortin receptors cloned and characterized (1,2). Subsequently, three other melanocortin receptor subtypes have been cloned and designated the MC3-R, MC4-R, and MC5-R. The MC1-R has been clearly demonstrated to be involved in pigmentation and animal coat coloration (3,4). The efficacy of melanocortin peptides at the MC1-R can be summarized as 4-norleucine, 7-d-phenylalanine (NDP-MSH) > α-MSH > ACTH >γ-MSH. With the availability of the cloned melanocortin receptors, several questions can now be studied. In vitro investigations using these cloned receptors may include identifying critical ligand features resulting in receptor selectivity, ligand residues responsible for differing efficacies, and how these ligand residues interact with the receptor for recognition and activation. In lieu of X-ray crystal structures, three-dimensional (3D) homology receptor modeling has become a tool to attempt to identify noteworthy ligand and receptor features. Furthermore, knowledge of the molecular mechanism responsible for the initial intracellular signal transduction cascade would be potentially important for the design of antagonists. This chapter is designed to attempt to address these issues from the available literature.


Ligand Affinity Melanocortin Receptor Ligand Binding Affinity Receptor Residue Melanocortin Peptide 
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  1. 1.
    Chhajlani, V. and Wikberg, J. E. S. (1992) Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett 309, 417–420.CrossRefGoogle Scholar
  2. 2.
    Mountjoy, K. G., Robbins, L. S., Mortrud, M. T., and Cone, R. D. (1992) The cloning of a family of genes that encode the melanocortin receptors. Science 257, 1248–1251.PubMedCrossRefGoogle Scholar
  3. 3.
    Cone, R. D., Lu, D., Kopula, S., Vage, D. I., Klungland, H., Boston, B., Chen, W., Orth, D. N., Pouton, C., and Kesterson, R. A. (1996) The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Progr. Norm. Res. 51, 287–318.Google Scholar
  4. 4.
    Robbins, L. S., Nadeau, J. H., Johnson, K. R., Kelly, M. A., Roselli—Rehfuss, L., Baack, E., Mountjoy, K. G., and Cone, R. D. (1993) Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72, 827–834.Google Scholar
  5. 5.
    Castrucci, A. M. L., Hadley, M. E., Sawyer, T. K., Wilkes, B. C., Al—Obeidi, F., Staples, D. J., DeVaux, A. E., Dym, O., Hintz, M. F., Riehm, J., Rao, K. R., and Hruby, V. J. (1989) a—Melanotropin: the minimal active sequence in the lizard skin bioassay. Gen. Comp. Endocrinol. 73, 157–163.Google Scholar
  6. 6.
    Haskell-Luevano, C., Shenderovich, M. D., Sharma, S. D., Nikiforovich, G. V., Hadley, M. E., and Hruby, V. J. (1995) Design, synthesis, biology and conformations of bicyclic a—melanotropin peptide analogues. J. Med. Chem. 38, 1736–1750.PubMedCrossRefGoogle Scholar
  7. 7.
    Eberle, A. N. (1988)The Melanotropins: Chemistry, Physiology and Mechanisms of Action,Karger, Basel.Google Scholar
  8. 8.
    Hadley, M. E. (1989)The Melanotropic Peptides: Source, Synthesis, Chemistry, Secretion and Metabolism; Vols. I—III. CRC Press, Boca Raton, FL.Google Scholar
  9. 9.
    Hruby, V. J., Wilkes, B. C., Hadley, M. E., Al—Obeidi, F., Sawyer, T. K., Staples, D. J., DeVaux, A., Dym, O., Castrucci, A. M., Hintz, M. F., Riehm, J. P., and Rao, K. R. (1987) a—Melanotropin: the minimal active sequence in the frog skin bioassay. J. Med. Chem. 30, 2126–2130.Google Scholar
  10. 10.
    Hruby, V. J., Wilkes, B. C., Cody, W. L., Sawyer, T. K., and Hadley, M. E. (1984) Melanotropins: structural, conformational and biological considerations in the development of superpotent and superprolonged analogs. Pept. Protein Rev. 3, 1–64.Google Scholar
  11. 11.
    Medzihradszky, K. (1982) The bio—organic chemistry of a—melanotropin. Medicinal Res. Rev. 2, 247–270.CrossRefGoogle Scholar
  12. 12.
    Vaudry, H. and Eberle, A. N. (1993)The melanotropic peptides. Ann. N. Y. Acad. Sci. 680.Google Scholar
  13. 13.
    Haskell-Luevano, C., Hendrata, S., North, C., Sawyer, T. K., Hadley, M. E., Hruby, V. J., Dickinson, C., and Gantz, I. (1997) Discovery of prototype peptidomimetic agonists at the human Melanocortin receptors MC 1-R and MC4-R. J. Med. Chem. 40, 2133–2139.PubMedCrossRefGoogle Scholar
  14. 14.
    Schiöth, H. B., Muceniece, R., Larsson, M., Mutulis, F., Szardenings, M., Prusis, P., Lindeberg, G., and Wikberg, J. E. S. (1997) Binding of cyclic and linear MSH core peptides to the melanocortin receptor subtypes. Eur. J. Pharm. 319, 369–373.CrossRefGoogle Scholar
  15. 15.
    Haskell-Luevano, C., Sawyer, T. K., Hendrata, S., North, C., Panahinia, L., Stum, M., Staples, D. J., Castrucci, A. M., Hadley, M. E., and Hruby, V. J. (1996) Truncation studies of a—melanotropin peptides identifies tripeptide analogues exhibiting prolonged agonist bioactivity. Peptides 17, 995–1002.PubMedGoogle Scholar
  16. 16.
    Buffy, J., Thody, A. J., Bleehen, S. S., and Mac Neil, S. (1992) a—MSH stimulates protein kinase c activity in murine b16 melanoma. J. Endocrinol 133, 333–340.Google Scholar
  17. 17.
    Konda, Y., Gantz, I., DelValle, J., Shimoto, Y., Miwa, H., and Yamada, T. (1994) Interaction of dual signal trandsuction pathways activated by the melanocortin-3 receptor. J. Biol. Chem. 269, 13,162–13, 166.Google Scholar
  18. 18.
    Abdel-Malek, Z. A., Kreutzfeld, K. L., Marwan, M. M., Hadley, M. E., Hruby, V. J., and Wilkes, B. C. (1985) Prolonged stimulation of S91 melanoma tyrosinase by [Nle°, r—Phe’]—substituted a—Melanotropins. Cancer Res. 45, 4735–4740.PubMedGoogle Scholar
  19. 19.
    Chen, W., Shields, T. S., Stork, P. J. S., and Cone, R. D. (1995) A colorimetric assay for measuring activation of Gs—and Gq—coupled signaling pathways. Anal. Biochem. 226, 349–354.PubMedCrossRefGoogle Scholar
  20. 20.
    Hadley, M. E., Anderson, B., Heward, C. B., Sawyer, T. K., and Hruby, V. J. (1981) Calcium—dependent prolonged effects on melanophores of [4—norleucine, 7—ram Phenylalanine]—a—melanotropin. Science 213, 1025–1027.PubMedCrossRefGoogle Scholar
  21. 21.
    Haskell-Luevano, C., Miwa, H., Dickinson, C., Hadley, M. E., Hruby, V. J., Yamada, T., and Gantz, I. (1996) Characterizations of the unusual dissociation properties of melanotropin peptides from the melanocortin receptor, hMC1-R. J. Med. Chem. 39, 432–435.PubMedCrossRefGoogle Scholar
  22. 22.
    Prusis, P., Frändberg, P.—A., Muceniece, R., Kalvinsh, I., and Wikberg, J. E. S. (1995) A three dimensional model for the interaction of MSH with the melanocortin-1 receptor. Biochem. Biophys. Res. Commun. 210, 205–210.PubMedCrossRefGoogle Scholar
  23. 23.
    Haskell-Luevano, C., Sawyer, T. K., Trumpp-Kallmeyer, S., Bikker, J., Humblet, C., Gantz, I., and Hruby, V. J. (1996) Three—dimensional molecular models of the hMC1-R melanocortin receptor: complexes with melanotropin peptide agonists. Drug Des. Discov. 14, 197–211.PubMedGoogle Scholar
  24. 24.
    Henderson, R., Baldwin, J. M., Ceska, T. A., Zemlin, F., Beckmann, E., and Downing, K. H. (1990) Model for the strucuture of bacteriorhodopsin based on high—resolution electron cryo—microscopy. J. Mol. Biol. 213, 899–929.PubMedCrossRefGoogle Scholar
  25. 25.
    Schertler, G. F. X., Villa, C., and Henderson, R. (1993) Projection structure of rhodopsin. Nature 362, 770–772.PubMedCrossRefGoogle Scholar
  26. 26.
    Schertler, G. F. X. and Hargrave, P. A. (1995) Projection structure of frog rhodopsin in two crystal forms. Proc. Natl. Acad. Sci. U. S. A. 92, 11,578–11, 582.Google Scholar
  27. 27.
    Schertler, G. F. X., Hargrave, P. A., and Unger, V. M. (1996) Three dimentional structure of rhodopsin obtained by electron cryomicroscopy. Invest. Ophthalmol. Visual Sci. 37, S805.Google Scholar
  28. 28.
    Schertler, G. F. X., Unger, V. M.., and Hargrave, P. A. (1995) The Structure of rhodopsin obtained by cryo-electron microscopy to 7 A resolution. Biophys. J. 68, A. 21Google Scholar
  29. 29.
    Unger, V. M. and Schertler, G. F. X. (1995) Low resolution structure of bovine rhodopsin determined by electron cryo—microscopy. Biophys. J. 68, 1776–1786.PubMedCrossRefGoogle Scholar
  30. 30.
    Davies, A., Schertler, G. F. X., Gowen, B. E., and Saibil, H. R. (1996) Projection structure of an inverterate rhodopsin. J. Struct. Biol. 117, 36–44.PubMedCrossRefGoogle Scholar
  31. 31.
    Unger, V. M., Hargrave, P. A., and Schertler, G. F. X. (1995) Localization of the transmembrane helices in the three—dimentsonal structure of frog rhodopsin. Biophys. J. 68, A330.CrossRefGoogle Scholar
  32. 32.
    Grigorieff, N., Ceska, T. A., Downing, K. H., Baldwin, J. M., and Henderson, R. (1996) Electron—crystallographic refinement of the structure of bacteriorhodopsin. J. Mol. Biol. 259, 393–421.PubMedCrossRefGoogle Scholar
  33. 33.
    Pebay-Peyroula, E., Rummel, G., Rosenbusch, J. P., and Landau, E. M. (1997) X-ray structure of bacteriorhodopsin at 2.5 angstroms from microcrystals grown in lipidic cubic phases. Science 277, 1676–1681.PubMedCrossRefGoogle Scholar
  34. 34.
    Unger, V. M., Hargrave, P. A., Baldwin, J. M., and Schertler, G. F. X. (1997) Arrangement of rhodopsin transmembrane a-helices. Nature 389, 203–206.PubMedCrossRefGoogle Scholar
  35. 35.
    Kimura, Y., Vassylyev, D. G., Miyazawa, A., Kidera, A., Matusuhima, M., Mitsuoka, K., Murata, K., Hirai, T., and Fujiyoshi, Y. (1997) Surface of bacteriorhodopsin revealed by high-resoluation electron crystallography. Nature 389, 206–211.PubMedCrossRefGoogle Scholar
  36. 36.
    Hutchins, C. (1994) Three-dimensional models of the D1 and D2 dopamine receptors. Endoc. J. 2, 7–23.Google Scholar
  37. 37.
    Hibert, M. F., Trumpp-Kallmeyer, S., Bruinvels, A., and Hoflack, J. (1991) Three-dimensional models of neurotransmitter G-binding protein-coupled receptors. Mol. Pharmacol. 40, 8–15.PubMedGoogle Scholar
  38. 38.
    Hoflack, J., Trumpp-Kallmeyer, S., and Hibert, M. (1994) Re-evaluation of bacteriorhodopsin as a model for G protein-coupled receptors. Trend Pharmacol. Sci. 15, 7–9.CrossRefGoogle Scholar
  39. 39.
    Trumpp-Kallmeyer, S., Hoflack, J., Bruinvels, A., and Hibert, M. (1992) Modeling of G-protein-coupled receptors: application to dopamine, adrenaline, serotonin, acetylcholine, and mammalian opsin receptors. J. Med. Chem. 35, 3448–3462.PubMedCrossRefGoogle Scholar
  40. 40.
    Marklund, L., Johansson Moller, M., Sandberg, K., and Anderson, L. (1996) A missense mutation in the gene for melanocyte-stimulating hormone receptor (MC 1-R) is associated with the chestnut coat color in horses. Mamm. Genome 7, 895–899.PubMedCrossRefGoogle Scholar
  41. 41.
    Kungland, H., Vage, K. I., Gomez-Raya, L., Adelsteinsson, S., and Lien, S. (1995) The role of melanocyte-stimulating hormone (MSH) receptor in bovine coat color determination. Mamm. Genome 6, 636–639.CrossRefGoogle Scholar
  42. 42.
    Vanetti, M., Schonrock, C., Meyerhof, W., and Hollt, V. (1994) Molecular cloning of a bovine MSH receptor which is highly expressed in the testis. FEBS Lett 348, 268–272.PubMedCrossRefGoogle Scholar
  43. 43.
    Lu, D., Haskell-Luevano, C., Vage, D. I., and Cone, R. D. (1999) Functional variants of the MSH receptor (MC1-R), agouti, and their effects on mammalian pigmentation, in Humana Press, Totowa, N. J. pp. 231–259.Google Scholar
  44. 44.
    Vage, D. I., Lu, D., Klungland, H., Lien, S., Adalsteinsson, S., and Cone, R. D. (1997) A non-epistatic Interaction of agouti and extension in the fox, Vulpes Vulpes. Nat. Genet. 15, 311–315.CrossRefGoogle Scholar
  45. 45.
    Takeuchi, S., Suzuki, S., Hirose, S., Yabuuchi, M., Sato, C., Yamamoto, H., and Takahashi, S. (1996) Molecular cloning and sequence analysis of the chick melanocortin 1-receptor gene. Biochem. Biophys. Acta 1306, 122–126.PubMedCrossRefGoogle Scholar
  46. 46.
    Baldwin, J. M. (1993) The probable arrangement of the helices in G protein-coupled receptors. EMBO J. 12, 1693–1703.PubMedGoogle Scholar
  47. 47.
    Mountjoy, K. G. (1994) The human melanocyte stimulating hormone receptor has evolved to become “super-sensitive” to melanocortin peptides. Mol. Cell. Endocrinol. 102, R7 - R11.PubMedCrossRefGoogle Scholar
  48. 48.
    Valverde, P., Healy, E., Jackson, I., Rees, J. L., and Thody, A. J. (1995) Variants of the melanocyte-stimulating hormaone receptor gene are associated with red hair and fair skin in humans. Nat. Genet. 11, 328–330.PubMedCrossRefGoogle Scholar
  49. 49.
    Koppula, S. V., Robbins, L. S., Lu, D., Baack, E., White, C. R., Swanson, N. A., and Cone, R. D. (1997) Identification of common polymorphisms in the coding sequence of the human MSH receptor (MC1-R) with possible biological effects. Hum. Mut. 9, 30–36.PubMedCrossRefGoogle Scholar
  50. 50.
    Lu, D., Vage, D. I., and Cone, R. D. (1999) A ligand—mimetic model for constitutive activation of the melanocortin-1 receptor. Mol. Endocrinol. 12, 592–604.CrossRefGoogle Scholar
  51. 51.
    Vage, D. I., Klungland, H., Lu, D., and Cone, R. D. (1999) Molecular and pharmacological characterization of dominant black coat color in sheep. Mamm. Genome 10, 39–43.PubMedCrossRefGoogle Scholar
  52. 52.
    Probst, W. C., Snyder, L. A., Schuster, D. I., Brosius, J., and Sealfon, S. C. (1992) Sequence alignment of the G—protein coupled receptor superfamily. DNA Cell Biol. 11, 1–20.PubMedCrossRefGoogle Scholar
  53. 53.
    Findlay, J. and Eliopoulos, E. (1990) Three—dimensional modelling of G protein—linked receptors. TiPS 11, 492–499.PubMedGoogle Scholar
  54. 54.
    Savarese, T. M. and Fraser, C. M. (1992) In vitro mutagenesis and the search for structure—function relationships among G protein—coupled receptors. Biochem. J. 283, 1–19.PubMedGoogle Scholar
  55. 55.
    Wess, J., Nanavati, S., Vogel, Z., and Maggio, R. (1993) Functional role of proline and tryptophan residues highly conserved among G—protein—coupled receptors studied by mutational analysis of the m3 muscarinic receptor. EMBOJ. 12, 331–338.Google Scholar
  56. 56.
    Hong, S., Ryu, K.—S., Oh, M.—S., Ji, I., and Ji, T. H. (1997) Roles of transmembrane prolines and proline—induced kinks of the lutropin/choriogonadotropin receptor. J. Biol. Chem. 272, 4166–4171.PubMedCrossRefGoogle Scholar
  57. 57.
    Perlman, J. H., Colson, A.—O., Wang, W., Bence, K., Osman, R., and Greshengorn, M. C. (1997) Interactions between conserved residues in transmembrane helices 1, 2, and 7 of the thyrotropin—releasing hormone receptor. J. Biol. Chem. 272, 11,937–11, 942.Google Scholar
  58. 58.
    Hunyady, L., Bor, M., Baukal, A. J., Balla, T., and Catt, K. J. (1996) A conserved nplfy sequence contributes to agonist binding and signal trandsuction but is not an internalization signal for the type 1 angiotensin ii receptor. J. Biol. Chem. 270, 16,602–16, 609.Google Scholar
  59. 59.
    Strosberg, A. D., Camoin, L., Blin, N., and Maigret, B. (1993) In receptors coupled to GTP—binding proteins, ligand binding and G—protein activation is a multistep dynamic process. Drug Des. Discov. 9, 199–211.PubMedGoogle Scholar
  60. 60.
    Berlose, J.—P., Convert, O., Brunissen, A., Chassaing, G., and La Vielle, S. (1994) Three—dimensional structure of the highly conserved seventh transmembrane domain of G—protein—coupled receptors. Eur. J. Biochem. 225, 827–843.PubMedCrossRefGoogle Scholar
  61. 61.
    Frändberg, P.—A., Muceniece, R., Prusis, P., Wikberg, J., and Chhajlani, V. (1994) Evidence for alternate points of attachment for a—MSH and its stereoisomer [Nle4, D—Phe7]—a—MSH at the melanocortin-1 receptor. Biochem. Biophys. Res. Commun. 202, 1266–1271.PubMedCrossRefGoogle Scholar
  62. 62.
    Ballesteros, J. A. and Weinstein, H. (1995) Integrated methods for the construction of three dimensional models and computational probing of structure—function relations in G—protein coupled receptors. Methods Neurosci. 25, 366–428.CrossRefGoogle Scholar
  63. 63.
    van Rhee, A. M. and Jacobson, K. A. (1996) Molecular architecture of G protein—coupled receptors. Drug Devel. Res. 37, 1–38.CrossRefGoogle Scholar
  64. 64.
    Haskell-Luevano, C., Miwa, H., Dickinson, C., Hruby, V. J., Yamada, T., and Gantz, I. (1994) Binding and cAMP studies of melanotropin peptides with the cloned human peripheral melanocortin receptor, hMC1-R. Biochem. Biophys. Res. Commun. 204, 1137–1142.PubMedCrossRefGoogle Scholar
  65. 65.
    Sawyer, T. K., Castrucci, A. M., Staples, D. J., Affholter, J. A., DeVaux, A. E., Hruby, V. J., and Hadley, M. E. (1993) Structure—activity relationships of [Nle4, D—Phe’] a—MSH: discovery of a tripeptidyl agonist exhibiting sustained bioactivity Ann. N. Y. Acad. Sci. 680, 597–599.PubMedCrossRefGoogle Scholar
  66. 66.
    Al-Obeidi, F., Hruby, V. J., Yaghoubi, N., Marwan, M. M., and Hadley, M. E. (1992) Synthesis and Biological activities of fatty acid conjugates of a cyclic lactam a—melanotropin. J. Med. Chem. 35, 118–123.PubMedCrossRefGoogle Scholar
  67. 67.
    Sahm, U. G., Olivier, G. W. J., Branch, S. K., Moss, S. H., and Pouton, C. W. (1994) Influence of a—MSH terminal amino acids on binding affinity and biological activity in melanoma cells. Peptides 15, 441–446.PubMedCrossRefGoogle Scholar
  68. 68.
    Sharma, S. D., Nikiforovich, G. V., Jiang, J., Castrucci, A. M., Hadley, M. E., and Hruby, V. J. (1992) A new class of positively charged melanotropin analogs: a new concept in peptide design. In Peptides, (Schneider, C. H. and Eberle, A. N., eds.) Escom, Leiden, pp. 95, 96.Google Scholar
  69. 69.
    Sharma, S. D., Nikiforovich, G. V., Jiang, J., Castrucci, A. M., Hadley, M. E., and Hruby, V. J. (1994) Cationized melanotropin analogues: structure—function relationships, in Peptides: Chemistry and Biology, ( Hodges, R. A. and Smith, J. A. eds.), ESCOM, Leiden, pp. 398–399.Google Scholar
  70. 70.
    Chaturvedi, D. N., Hruby, V. J., Castrucci, A. M., Kreutzfeld, K. L., and Hadley, M. E. (1985) Synthesis and biological evaluation of the superagonist [Nachlorotriazinylaminofluorescein—Ser’, Nle4, D—Phe’]—a—MSH. J. Pharm. Sci. 74, 237–240.PubMedCrossRefGoogle Scholar
  71. 71.
    Chaturvedi, D. N., Knittel, J. J., Hruby, V. J., de L. Castrucci, A. M., and Hadley, M. E. (1984) Synthesis and biological actions of highly potent and prolonged acting biotin—labeled melanotropins. J. Med. Chem. 27, 1406–1410.Google Scholar
  72. 72.
    Castrucci, A. M. L., Hadley, M. E., Sawyer, T. K., and Hruby, V. J. (1984) Enzymological studies of melanotropins. Comp. Biochem. Physiol. 78B, 519–524.CrossRefGoogle Scholar
  73. 73.
    Sawyer, T. K., Sanfillippo, P. J., Hruby, V. J., Engel, M. H., Heward, C. B., Burnett, J. B., and Hadley, M. E. (1980) 4—Norleucine, 7—D—phenylalanine—a—melanocytestimulating hormone: a highly potent a—melanotropin with ultra long biological activity. Proc. Natl. Acad. Sci. U. S. A. 77, 5754–5758.Google Scholar
  74. 74.
    Al-Obeidi, F., Hadley, M. E., Pettitt, B. M., and Hruby, V. J. (1989) Design of a new Class of superpotent cyclic a—melanotropins based on quenched dynamic stimulations. J. Am. Chem. Soc. 111, 3413–3416.CrossRefGoogle Scholar
  75. 75.
    Al-Obeidi, F., Castrucci, A. M., Hadley, M. E., and Hruby, V. J. (1989) Potent and prolonged acting cyclic lactam analogues of a—melanotropin: design based on molecular dynamics. J. Med. Chem. 32, 2555–2561.PubMedCrossRefGoogle Scholar
  76. 76.
    Mitchell, J. B. O., Nandi, C. L., McDonald, I. K., Thornton, J. M., and Price, S. L. (1994) Amino/aromatic interactions in proteins: is the evidence stacked against hydrogen bonding? J. Mol. Biol. 239, 315–331.PubMedCrossRefGoogle Scholar
  77. 77.
    Levitt, M. and Perutz, M. (1988) Aromatic rings act as hydrogen bond acceptors. J. Mol. Biol. 201, 751–754.PubMedCrossRefGoogle Scholar
  78. 78.
    Burley, S. K. and Petsko, G. A. (1986) Amino—aromatic interactions in proteins. FEBS Lett. 203, 139–143.PubMedCrossRefGoogle Scholar
  79. 79.
    Burley, S. and Petsko, G. (1988) Weakly polar interactions in proteins. Adv. Protein Chem 39, 125–189.PubMedCrossRefGoogle Scholar
  80. 80.
    Flocco, M. and Mowbray, S. (1994) Planar stacting interactions of arginine and aromatic side—charins in proteins. J. Mol. Biol. 235, 709–717.PubMedCrossRefGoogle Scholar
  81. 81.
    Ajay and Murcko, M. A. (1995) Computational methods to predict binding free energy in ligand-receptor complexes. J. Med. Chem. 38, 4953–4967.PubMedCrossRefGoogle Scholar
  82. 82.
    Cuatrecasas, P. and Hollenberg, M. D. (1976) Membrane receptors and hormone action. In Advances in Protein Chemistry ( Anfinsei, C. B., Edsall, J. T., and Richards, F. M., eds.) Academic Press, New York, pp. 251–451.Google Scholar
  83. 83.
    Yamamura, H. I., Enna, S. J., and Kuhar, M. J., Methods in Neurotransmitter Receptor Analysis, Raven Press: New York, (1990).Google Scholar
  84. 84.
    Williams, M., Glennon, R. A., and Timmermans, P. B. M. W. M. Receptor Pharmacology and Function; Marcel Dekker, New York, (1989).Google Scholar
  85. 85.
    Hulme, E. C. Receptor-Ligand Interactions: A Practical Approach; IRL Press: New York, (1992).Google Scholar
  86. 86.
    Ramachandran, G. N. and Sasisekharan, V. (1968) Conformation of polypeptides and proteins. Adv. Protein. Chem. 23, 283–437.PubMedCrossRefGoogle Scholar
  87. 87.
    Pimentel, G. C. and McClellan (1960)The Hydrogen Bond. Freeman, London. pp. 282–288.Google Scholar
  88. 88.
    Schulz, G. E. and Schirmer, R. H. (1979)Principles of Protein Structure. Springer-Verlag, New York, pp. 20–28.Google Scholar
  89. 89.
    Schwartz, T. W., Gether, U., Schambye, H. T., and Hjorth, S. A. (1995) Molecular mechanism of action of non-peptide ligands for peptide receptors. Curr. Pharm. Des. 1, 325–342.Google Scholar
  90. 90.
    Chhajlani, V., Xu, X. L., Blauw, J., and Sudarshi, S. (1996) Identification of ligand binding residues in extracellular loops of the melanocortin 1 receptor. Biochem. Biophys. Res. Commun. 219, 521–525.PubMedCrossRefGoogle Scholar
  91. 91.
    Schiöth, H. B., Muceniece, R., Szardenings, M., Prusis, P., Lindeberg, G., Sharma, S. D., Hruby, V. J., and Wikberg, J. E. (1997) Characterisation of D117A and H260A mutations in the melanocortin 1 receptor. Mol. Cell. Endocrinol. 126, 213–219.PubMedCrossRefGoogle Scholar
  92. 92.
    Yang, Y.-K., Dickinson, C., Haskell-Luevano, C., and Gantz, I. (1997) Molecular basis for the interaction of [Nle4, D-Phe’] melanocyte stimulating hormone with the human moleanocortin-1 receptor (melanocyte a-MSH receptor). J. Biol. Chem. 272, 23000–23010.PubMedCrossRefGoogle Scholar
  93. 93.
    Haskell-Luevano, C., Nikiforovich, G. V., Sharma, S.D., Yang, Y.-K., Dickinson, C., Hruby, V. J., and Gantz, I. (1997) Biological and conformational evaluation of stereochemical modifications using the template melanotropin peptide, Ac-Nlec[Asp-His-Phe-Arg-Trp-Ala-Lys]-NH2, on human melanocortin receptors. J. Med. Chem. 40, 1738–1748.PubMedCrossRefGoogle Scholar
  94. 94.
    Haskell-Luevano, C., Boteju, L. W., Miwa, H., Dickinson, C., Gantz, I., Yamada, T., Hadley, M. E., and Hruby, V. J. (1995) Topographical modifications of melanotropin peptide analogues with (3-methyltryptophan isomers at position 9 leads to differential potencies and prolonged biological activities. J. Med. Chem. 38, 4720–4729.PubMedCrossRefGoogle Scholar
  95. 95.
    Hruby, V. J., Lu, D., Sharma, S. D., Castrucci, A. M. L., Kesterson, R. A., AlObeidi, F. A., Hadley, M. E., and Cone, R. D. (1995) Cyclic lactam a-melanotropin analogues of Ac-Nle4-c[Asp5, D-Phe’, Lys101-a-MSH(4–10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J. Med. Chem. 38, 3454–3461.PubMedCrossRefGoogle Scholar
  96. 96.
    Huang, R.-R. C., Vicario, P. P., Strader, C. D., and Fong, T. M. (1995) Identification of residues involved in ligand binding to the neurokinin-2 receptor. Biochemistry 34, 10, 048–10, 055.Google Scholar
  97. 97.
    Chini, B., Mouillac, B., Ala, Y., Balestre, M.—N., Trumpp—Kallmeyer, S., Hoflack, J., Elands, J., Hibert, M., Manning, M., Jard, S., and Barberis, C. (1995) Tyr115 is the key residue for determining agonist selectivity in the v 1 a vasopressin receptor. EMBO J. 14, 2176–2182.Google Scholar
  98. 98.
    Kaupmann, K., Bruns, C., Raulf, F., Weber, H. P., Mattes, H., and Lübbert, H. (1995) two amino acids, located in transmembrane domains vi and vii, determine the selectivity of the peptide agonist sms 201–995 for the sstr2 somatostatin receptor. EMBO J. 14, 727–735.Google Scholar
  99. 99.
    Mouillac, B., Chini, B., Balestre, M.—N., Elands, J., Trumpp—Kallmeyer, S., Hoflack, J., Hibert, M., Jard, S., and Barberis, C. (1995) The binding site of neuropeptide vasopressin VIa receptor: evidence for a major localization within trans-membrane regions. J. Biol. Chem. 270, 25, 771–25, 777.Google Scholar
  100. 100.
    Lu, D. Doctoral Thesis, Oregon Health Science University, 1997.Google Scholar
  101. 101.
    Robinson, P. R., Cohen, G. B., Zhukovsky, E. A., and Oprian, D. D. (1992) Constitutively active mutants of rhodopsin. Neuron 9, 719–725.PubMedCrossRefGoogle Scholar
  102. 102.
    Cohen, G. B., Oprian, D. D., and Robinsin, P. R. (1992) Mechanism of activation and inactivation of opsin: role of Glul 13 and Lys296. Biochemistry 31, 12, 592–12, 601.Google Scholar
  103. 103.
    Kenakin, T. (1996) Receptor conformation induction versus selection: all part of the same energy landscape. Trends Pharmacol. Sci. 17, 190–191.CrossRefGoogle Scholar
  104. 104.
    Kenakin, T. (1995) Agonist—receptor efficacy i: mechanisms of efficacy and receptor promiscuity. Trends Pharmacol. Sci. 16, 188–192.PubMedCrossRefGoogle Scholar
  105. 105.
    Kenakin, T. (1995) Agonist—receptor efficacy ii: atonist trafficking of receptor signals. Trends Pharmacol. Sci. 16, 232–238.PubMedCrossRefGoogle Scholar
  106. 106.
    Bond, R. A., Leff, P., Johnson, T. D., Milano, C. A., Rockman, H. A., McMinn, T. R., Apparsundaram, S., Hyek, M. F., Kenakin, T. P., Allen, L. F., and Lefkowitz, R. J. (1995) Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the b2—adrenoceptor. Nature 374, 272–276.PubMedCrossRefGoogle Scholar
  107. 107.
    Elling, C. E., Nielsen, S. M., and Schwartz, T. W. (1995) conversion of antagonist—binding site to metal—ion site in the tachykinin NK-1 receptor. Nature 374, 74–77.Google Scholar
  108. 108.
    Thristrup, K., Elling, C. E., Hjorth, S. A., and Schwartz, T. W. (1996) Construction of a high affinity zinc switch in the x—opioid receptor. J. Biol. Chem. 271, 7875–7878.CrossRefGoogle Scholar
  109. 109.
    Cotecchia, S., Exum, S., Caron, M. G., and Lefkowitz, R. J. (1990) Regions of the al—adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function. Proc. Natl. Acad. Sci. U. S. A. 87, 2896–2900.PubMedCrossRefGoogle Scholar
  110. 110.
    Ren, Q., Kurose, H., Lefkowitz, R. J., and Cotecchia, S. (1993) Constitutively active mutants of the a2—adrenergic receptor. J. Biol. Chem. 268, 16,483–16, 487.Google Scholar
  111. 111.
    Samama, P., Cotecchai, S., Costa, T., and Lefkowitz, R. J. (1993) A mutation—induced activated state of the (32—adrenergic receptor. extending the ternary complex model. J. Biol. Chem. 268, 4625–4636.PubMedGoogle Scholar
  112. 112.
    Scheer, A., Fanelli, F., Costa, T., De Benedetti, P. G., and Cotecchia, S. (1996) Constitutively active mutants of the alpha 113—adrenergic receptor: role of highly conserved polar amino acids in receptor activation. EMBO J. 15, 3566–3578.PubMedGoogle Scholar
  113. 113.
    Oliveira, L., Paiva, A. C. M., Sander, C., and Vriend, G. (1994) A common step for signal transduction in G protein—coupled receptors. TiPS 15, 170–172.PubMedGoogle Scholar

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© Springer Science+Business Media New York 2000

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  • Carrie Haskell-Luevano

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