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Titolo:
Conformation of the core sequence in melanocortin peptides directs selectivity for the melanocortin MC3 and MC4 receptors
Autore:
Oosterom, J; Nijenhuis, WAJ; Schaaper, WMM; Slootstra, J; Meloen, RH; Gispen, WHH; Burbach, JPH; Adan, RAH;
Indirizzi:
Univtrecht,t, Rudolf Magnus Inst Neurosci, Dept Med Pharmacol, NL-3508 TA U Univ Utrecht Utrecht Netherlands NL-3508 TA Med Pharmacol, NL-3508 TA U Inst Anim Sci & Hlth, NL-8200 AB Lelystad, Netherlands Inst Anim Sci & Hlth Lelystad Netherlands NL-8200 AB lystad, Netherlands
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 24, volume: 274, anno: 1999,
pagine: 16853 - 16860
SICI:
0021-9258(19990611)274:24<16853:COTCSI>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
MELANOCYTE-STIMULATING HORMONE; ALPHA-MSH ANALOGS; MOLECULAR-CLONING; BIOLOGICAL-ACTIVITY; ADENYLATE-CYCLASE; RAT HYPOTHALAMUS; GAMMA-MSH; MELANOTROPIN; BINDING; EXPRESSION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
49
Recensione:
Indirizzi per estratti:
Indirizzo: Adan, RAH UnivGUtrecht, Rudolf Magnus Inst Neurosci, Fac Med, Univ Weg 100, NL-3584 C Univ Utrecht Univ Weg 100 Utrecht Netherlands NL-3584 CG 3584 C
Citazione:
J. Oosterom et al., "Conformation of the core sequence in melanocortin peptides directs selectivity for the melanocortin MC3 and MC4 receptors", J BIOL CHEM, 274(24), 1999, pp. 16853-16860

Abstract

Melanocortin peptides regulate a variety of physiological processes. Five melanocortin receptors (MC-R) have been cloned and the MC3R and MC4R are the main brain MC receptors. The aim of this study was to identify structuralrequirements in both ligand and receptor that determine gamma-melanocyte-stimulating hormone (MSH) selectivity for the MC3R versus the MC4R, Substitution of Asp(10) in [Nle(4)]Lys-gamma(2)-MSH for Gly(10) from [Nle(4)]alpha-MSH, increased both activity and affinity for the MC4R while the MC3R remained unaffected. Analysis of chimeric MC3R/MC4Rs and mutant MC4Rs showed that Tyr(268) Of the MC4R mainly determined the low affinity for [Nle(4)]Lys-gamma(2)-MSH. The data demonstrate that Asp(10) determines selectivity for the MC3R, however, not through direct side chain interactions, but probably by influencing how the melanocortin core sequence is presented to the receptor-binding pocket. This is supported by mutagenesis of Tyr(268) to lie in the MC4R which increased affinity and activity for [Nle(4)]Lys-gamma(2)-MSH, but decreased affinity for two peptides with constrained cyclic structureof the melanocortin core sequence, MT-II and [D-Tyr(4)]MT-II, that also displayed lower affinity for the MC3R. This study provides a general concept for peptide receptor selectivity, in which the major determinant for a selective receptor interaction is the conformational presentation of the core sequence in related peptides to the receptor-binding pocket.

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Documento generato il 21/09/20 alle ore 12:29:18