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Titolo:
MOLECULAR-BASIS FOR THE INTERACTION OF [NLE(4),D-PHE(7)]MELANOCYTE STIMULATING HORMONE WITH THE HUMAN MELANOCORTIN-1 RECEPTOR (MELANOCYTE ALPHA-MSH RECEPTOR)
Autore:
YANG YK; DICKINSON C; HASKELLLUEVANO C; GANTZ I;
Indirizzi:
UNIV MICHIGAN,SCH MED,DEPT SURG ANN ARBOR MI 48109 UNIV MICHIGAN,SCH MED,DEPT SURG ANN ARBOR MI 48109 VET ADM MED CTR ANN ARBOR MI 48109 UNIV MICHIGAN,SCH MED,DEPT INTERNAL MED ANN ARBOR MI 48109 UNIV MICHIGAN,SCH MED,DEPT PEDIAT ANN ARBOR MI 48109
Titolo Testata:
The Journal of biological chemistry
fascicolo: 37, volume: 272, anno: 1997,
pagine: 23000 - 23010
SICI:
0021-9258(1997)272:37<23000:MFTIO[>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
MELANOTROPIN PEPTIDES; LIGAND-BINDING; IDENTIFICATION; RESIDUES; PROTEINS; POTENT; DESIGN; HMC1R; MODEL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
26
Recensione:
Indirizzi per estratti:
Citazione:
Y.K. Yang et al., "MOLECULAR-BASIS FOR THE INTERACTION OF [NLE(4),D-PHE(7)]MELANOCYTE STIMULATING HORMONE WITH THE HUMAN MELANOCORTIN-1 RECEPTOR (MELANOCYTE ALPHA-MSH RECEPTOR)", The Journal of biological chemistry, 272(37), 1997, pp. 23000-23010

Abstract

The melanocortin-1 receptor (MC1R) is a seven-transmembrane (TM) G-protein-coupled receptor whose natural ligands are the melanocortin peptides, adrenocorticotropic hormone, and alpha-, beta-, gamma- melanocyte stimulating hormone (MSH). To test a previously constructed three-dimensional model of the molecular interaction between the long-acting, superpotent alpha-MSH analog [Nle(4),D-Phe(7)]MSH (NDP-MSH) and the human MC1R we examined the effects of site-directed receptor mutagenesison 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 alpha-MSH, gamma-MSH, and -[Asp(5),His(6),D-Phe(7),Arg(8),Trp(9),Lys(10)]NH2 (MT-II). Mutagenesis of acidic receptor residues Glu(94) in TM2 and Asp(117) or Asp(121) in TM3 significantly altered the binding affinity and potency of all four agonists suggesting that these receptor residues are importantto the ligand-receptor interactions of all. A disproportionate changein 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 constructD121K) also implicates these residues in receptor activation. In addition, results from the individual mutation of aromatic receptor residues Phe(175), Phe(196), and Phe(357), and simultaneous mutation of multiple TM4, -5, and -6 tyrosine and phenylalanine residues suggests thataromatic-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 nad the hMC1R.

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Documento generato il 20/09/20 alle ore 00:05:30