Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor
Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor
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DOI：
10.1021/jm0506928
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发表时间：
2006-01-26
影响因子：
7.3
通讯作者：
Struthers, RS
中科院分区：
文献类型：
--
作者：
Betz, SF;Reinhart, GJ;Struthers, RS
人促性腺激素释放激素受体（GnRH-R）的肽激动剂和拮抗剂广泛用于治疗一系列生殖激素相关疾病。最近，非肽，口服可用的GnRH-R拮抗剂已经出现了几个化学类别。要了解一个相对较大的肽结合口袋可以识别众多的非肽配体，我们进行了系统的映射GnRH-R残基参与结合的三个非肽拮抗剂。由跨膜螺旋6和7的细胞外部分、细胞外环3和N-末端结构域组成的区域显著促进了非肽拮抗剂结合。然而，每个分子的影响，在这些地区的残基的不同子集，表明每个似乎占据不同的，部分重叠的亚区内更广泛的肽结合，口袋。而且。得到的受体相互作用图谱为开始协调各种非肽和肽系列之间的结构-活性关系提供了基础，并有助于设计改进的治疗剂。
Peptide agonists and antagonists of the human gonadotropin-releasing, hormone receptor (GnRH-R) are widely used to treat a range of reproductive hormone related diseases. Recently, nonpeptide, orally available GnRH-R antagonists have emerged from several chemical classes. To understand how a relatively large peptide-binding pocket can recognize numerous nonpeptide ligands, we undertook a systematic mapping of GnRH-R residues involved in the binding of three nonpeptide antagonists. A region composed of the extracellular portions of transmembrane helices 6 and 7, extracellular loop 3, and the N-terminal domain significantly contributed to nonpeptide antagonist binding. However, each molecule was affected by a different subset of residues in these regions, indicating that each appears to occupy distinct, partially overlapping subregions within the more extensive peptide-binding, pocket. Moreover. the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between vari ous nonpeptide and peptide series and facilitate the design of improved therapeutic agents.