当前位置： SCI文献检索 > BIOCHEMISTRY期刊下所有文献 > Molecular interactions of nonpeptide agonists and antagonists with the melanocortin-4 receptor.

Molecular interactions of nonpeptide agonists and antagonists with the melanocortin-4 receptor.

Abstract：

:The melanocortin-4 (MC4) receptor is a potential therapeutic target for obesity and cachexia, for which nonpeptide agonists and antagonists are being developed, respectively. The aim of this study was to identify molecular interactions between the MC4 receptor and nonpeptide ligands, and to compare the mechanism of binding between agonist and antagonist ligands. Nonpeptide ligand interaction was affected by mutations that reduce peptide ligand binding (D122A, D126A, S190A, M200A, F261A, and F284A), confirming overlapping binding determinants for peptide and nonpeptide ligands. The common halogenated phenyl group of nonpeptide ligands was a determinant of F261A and F284A mutations' affinity-reducing effect, implying this group interacts with the aromatic side chains of these residues. All affected compounds contain this group, the mutations reduced binding of 2,4-dichloro-substituted compounds more than 4-chloro-substituted-compounds, and F284A mutation eliminated the affinity-enhancing effect of 2-chloro-substitution. F261A and F284A mutations reduced the affinity of antagonists more than agonists, suggesting that the stronger ligand interaction with these residues, the lower the ligand efficacy. Supporting this hypothesis, F261A mutation increased the efficacy of nonpeptide antagonist and partial agonist ligands. D122A and D126A mutations reduced nonpeptide ligand interaction. Removing the ligands' derivatized amide group eliminated the effect of the mutations. Interaction of agonists, which bear a common amine within this group, was strongly reduced by D126A mutation (550-3300-fold), suggesting an electrostatic interaction between the amine and the acidic group of D126. These postulated interactions with aromatic and acidic regions of the MC4 receptor are consistent with a molecular model of the receptor. Furthermore, the strength of interaction with the aromatic pocket, and potentially the acidic pocket, controls the signaling efficacy of the ligand.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Fleck BA,Chen C,Yang W,Huntley R,Markison S,Nickolls SA,Foster AC,Hoare SR

doi

10.1021/bi051316s

subject

Has Abstract

pub_date

2005-11-08 00:00:00

pages

14494-508

issue

eissn

0006-2960

issn

1520-4995

journal_volume

pub_type

杂志文章

在线工具

Molecular interactions of nonpeptide agonists and antagonists with the melanocortin-4 receptor.