TY - JOUR
T1 - Molecular basis for the interaction of [Nle4,D-Phe7]melanocyte stimulating hormone with the human melanocortin-1 receptor (melanocyte α- MSH receptor)
AU - Yang, Ying Kui
AU - Dickinson, Chris
AU - Haskell-Luevano, Carrie
AU - Gantz, Ira
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 1997
Y1 - 1997
N2 - The melanocortin-1 receptor (MC1R) is a seven-transmembrane (TM) G- protein-coupled receptor whose natural ligands are the melanocortin peptides, adrenocorticotropic hormone, and α-, β-, and γ- melanocyte stimulating hormone (MSH). To test a previously constructed three-dimensional model of the molecular interaction between the long-acting, superpotent α-MSH analog [Nle4,D-Phe7]MSH (NDP-MSH) and the human MC1R we examined the effects of site-directed receptor mutagenesis on the binding affinity and potency of NDP-MSH. In addition, we also examined the effects of these same mutations on the binding affinity and potency of the structurally related agonists α- MSH, γ-MSH, and Ac-Nle4-cyclic-[Asp5,His6,D- Phe7,Arg8,Trp9,Lys10]NH2 (MT-II). Mutagenesis of acidic receptor residues Glu94 in TM2 and Asp117 or Asp121 in TM3 significantly altered the binding affinity and potency of all four agonists suggesting that these receptor residues are important to the ligand-receptor interactions of all. A disproportionate change in agonist potency versus affinity observed with simultaneous mutation of these acidic residues (mutant constructs D117A/D121A or E94A/D117A/D121A) or introduction of a single positive charge (mutant construct D121K) also implicates these residues in receptor activation. In addition, results from the individual mutation of aromatic receptor residues Phe175, Phe196, and Phe257, and simultaneous mutation of multiple TM4, -5, and -6 tyrosine and phenylalanine residues suggests that aromatic-aromatic ligand-receptor interactions also participate in binding these melanocortins to the MC1R. These experiments appear to have identified some of the critical receptor residues involved in the ligand- receptor interactions between these melanocortins and the hMC1R.
AB - The melanocortin-1 receptor (MC1R) is a seven-transmembrane (TM) G- protein-coupled receptor whose natural ligands are the melanocortin peptides, adrenocorticotropic hormone, and α-, β-, and γ- melanocyte stimulating hormone (MSH). To test a previously constructed three-dimensional model of the molecular interaction between the long-acting, superpotent α-MSH analog [Nle4,D-Phe7]MSH (NDP-MSH) and the human MC1R we examined the effects of site-directed receptor mutagenesis on the binding affinity and potency of NDP-MSH. In addition, we also examined the effects of these same mutations on the binding affinity and potency of the structurally related agonists α- MSH, γ-MSH, and Ac-Nle4-cyclic-[Asp5,His6,D- Phe7,Arg8,Trp9,Lys10]NH2 (MT-II). Mutagenesis of acidic receptor residues Glu94 in TM2 and Asp117 or Asp121 in TM3 significantly altered the binding affinity and potency of all four agonists suggesting that these receptor residues are important to the ligand-receptor interactions of all. A disproportionate change in agonist potency versus affinity observed with simultaneous mutation of these acidic residues (mutant constructs D117A/D121A or E94A/D117A/D121A) or introduction of a single positive charge (mutant construct D121K) also implicates these residues in receptor activation. In addition, results from the individual mutation of aromatic receptor residues Phe175, Phe196, and Phe257, and simultaneous mutation of multiple TM4, -5, and -6 tyrosine and phenylalanine residues suggests that aromatic-aromatic ligand-receptor interactions also participate in binding these melanocortins to the MC1R. These experiments appear to have identified some of the critical receptor residues involved in the ligand- receptor interactions between these melanocortins and the hMC1R.
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U2 - 10.1074/jbc.272.37.23000
DO - 10.1074/jbc.272.37.23000
M3 - Article
C2 - 9287296
AN - SCOPUS:0030761093
VL - 272
SP - 23000
EP - 23010
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 37
ER -