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Titolo:
Molecular determinants of ligand binding to the human melanocortin-4 receptor
Autore:
Yang, Y; Fong, TM; Dickinson, CJ; Mao, C; Li, JY; Tota, MR; Mosley, R; Van der Ploeg, LHT; Gantz, I;
Indirizzi:
Univ Michigan, Sch Med, Dept Gen Surg, Ann Arbor, MI 48109 USA Univ Michigan Ann Arbor MI USA 48109 pt Gen Surg, Ann Arbor, MI 48109 USA Univ Michigan, Sch Med, Dept Pediat, Ann Arbor, MI 48109 USA Univ Michigan Ann Arbor MI USA 48109 Dept Pediat, Ann Arbor, MI 48109 USA Ann Arbor Vet Adm Hosp, Ann Arbor, MI 48109 USA Ann Arbor Vet Adm Hosp Ann Arbor MI USA 48109 sp, Ann Arbor, MI 48109 USA Merck Res Labs, Rahway, NJ 07065 USA Merck Res Labs Rahway NJ USA 07065Merck Res Labs, Rahway, NJ 07065 USA
Titolo Testata:
BIOCHEMISTRY
fascicolo: 48, volume: 39, anno: 2000,
pagine: 14900 - 14911
SICI:
0006-2960(200012)39:48<14900:MDOLBT>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
AGOUTI-RELATED PROTEIN; MELANOCYTE-STIMULATING-HORMONE; ALPHA-MELANOTROPIN; IN-VIVO; ANTAGONIST; CLONING; NEURONS; EXPRESSION; OBESITY; ANALOGS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
34
Recensione:
Indirizzi per estratti:
Indirizzo: Gantz, I Univ Michigan, Sch Med, Dept Gen Surg, Ann Arbor, MI 48109 USA Univ Michigan Ann Arbor MI USA 48109 rg, Ann Arbor, MI 48109 USA
Citazione:
Y. Yang et al., "Molecular determinants of ligand binding to the human melanocortin-4 receptor", BIOCHEM, 39(48), 2000, pp. 14900-14911

Abstract

To elucidate the molecular basis for the interaction of ligands with the human melanocortin-4, receptor (hMC4R), agonist structure-activity studies and receptor point mutagenesis were pet-formed. Structure-activity studies of [Nle(4),D-Phe(7)]-alpha -melanocyte stimulating hormone (NDP-MSH) identified D-Phe7-Arg8-Trp9 as the minimal NDP-MSH fragment that possesses full agonist efficacy at the hMC4R. In an effort to identify receptor residues that might interact with amino acids in this tripeptide sequence 24 hMC4R transmembrane (TM) residues were mutated (the rationale for choosing specific receptor residues for mutation is outlined in the Results section). Mutationof TM3 residues D122 and D126 and TM6 residues F261 and H264 decreased thebinding affinity of NDP-MSH 5-fold or greater, thereby identifying these receptor residues as sites potentially involved in the sought after ligand-receptor interactions. By examination of the binding affinities and potencies of substituted NDP-MSH peptides at receptor mutants, evidence was found that core melanocortin peptide residue Arg8 interacts at a molecular level with hMC4R TM3 residue D122. TM3 mutations were also observed to decrease the binding of hMC4R antagonists. Notably, mutation of TM3 residue D126 to alanine decreased the binding affinity of AGRP (87-132), a C-terminal derivative of the endogenous melanocortin antagonist, 8-fold, and simultaneous mutations D122A/D126A completely abolished AGRP (87-132) binding. In addition,mutation of TM3 residue D122 or D126 decreased the binding affinity of hMC4R antagonist SHU 9119. These results provide further insight into the molecular determinants of hMC4R ligand binding.

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Documento generato il 28/09/20 alle ore 15:07:38