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Titolo:
Minimization of MC1R selectivity by modification of the core structure of alpha-MSH-ND
Autore:
Lim, SK; Li, SZ; Lee, CH; Yoon, CJ; Baik, JH; Lee, W;
Indirizzi:
Yonsei Univ, Coll Med, Dept Internal Med, Div Endocrinol, Seoul 120752, South Korea Yonsei Univ Seoul South Korea 120752 docrinol, Seoul 120752, South Korea Yonsei Univ, Coll Sci, Dept Biochem, Seoul 120749, South Korea Yonsei Univ Seoul South Korea 120749 Biochem, Seoul 120749, South Korea Catholic Univ, Coll Sci, Dept Chem, Puchon City, South Korea Catholic Univ Puchon City South Korea pt Chem, Puchon City, South Korea Yonsei Univ, Coll Med, Med Res Ctr, Mol Biol Lab, Seoul 120752, South Korea Yonsei Univ Seoul South Korea 120752 Biol Lab, Seoul 120752, South Korea
Titolo Testata:
CHEMISTRY & BIOLOGY
fascicolo: 9, volume: 8, anno: 2001,
pagine: 857 - 870
SICI:
1074-5521(200109)8:9<857:MOMSBM>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
MELANOCYTE-STIMULATING HORMONE; MOLECULAR-CLONING; MELANOCORTIN RECEPTORS; BIOLOGICAL-ACTIVITY; NMR-SPECTROSCOPY; ANALOGS; MELANOTROPIN; BINDING; MODEL; EXPRESSION;
Keywords:
melanocortin receptor; binding affinity; cAMP-generating activity; nuclear magnetic resonance; type I beta-turn; homology modeling;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Lim, SK Yonsei Univ, Coll Med, Dept Internal Med, Div Endocrinol, 134 Shinchon Dong, Seoul 120752, South Korea Yonsei Univ 134 Shinchon Dong Seoul South Korea 120752 outh Korea
Citazione:
S.K. Lim et al., "Minimization of MC1R selectivity by modification of the core structure of alpha-MSH-ND", CHEM BIOL, 8(9), 2001, pp. 857-870

Abstract

Background: Melanocortin, through its distinct receptor subtypes, has manydifferent effects. Receptor-selective ligands are required to reduce the undesirable effects of melanocortin. To investigate which conformation is preferable to a given melanocortin receptor subtype, a structural and functional analysis of the ligand-receptor interactions was made by studying the biological activity, the nuclear magnetic resonance structures, and the patterns of the ligand-receptor interaction for each receptor subtype by homology modeling analysis. Results: Among the several analogues examined, [Gln(6)] alpha -melanocyte-stimulating hormone (MSH)-ND was found to have 10000 times less biological activity than alpha -MSH-ND for the MC1R, whereas. the potencies of both oligopeptides were comparable in both the melanocortin-3 receptor (MC3R) and MC4R. [Gln(6)]alpha -MSH-ND exhibited a type I' beta -turn that was similarto the type I alpha -turn structure of alpha -MSH-ND. However, a remarkable structural difference was observed with respect to the side chain orientations of the sixth and seventh residues of [Gln(6)]-MSH-ND, which were found to be mirror images of alpha -MSH-ND. By homology modeling analysis, the His(6) of alpha -MSH-ND was found to interact with the TM2 regions of all three receptors (Glu(94) of MC1R, Glu(94) of MC3R, and Glu(100) of MC4R), but [Gln(6)]alpha -MSH-ND did not. The phenyl ring of the D-Phe(7) residue of[Gln(6)]alpha -MSH-ND revealed an interaction with the TM3 regions of boththe MC3R and MC4R. (Ser(122) of MC3R or Ser(127) of MC4R). However, in theMC1R, these serine residues corresponded to Val(122). which contains two methyl groups that induce steric hindrance with D-Phe(7) of [Gln(6)]alpha -MSH-ND. This is a possible explanation for the biological activity of [Gln(6)]alpha -MSH-ND for the MC1R being significantly lower than that for eitherthe MC3R or MC4R. Conclusions: Minimization of the MC1R selectivity whilst preserving its comparable potency for both the MC3R and MC4R could be achieved by modifying the D-Phe(7) orientation of alpha -MSH-ND, while maintaining the 'type I beta -turn'-like structure. (C) 2001 Elsevier Science Ltd. All rights reserved.

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Documento generato il 31/10/20 alle ore 00:03:43