Pharmacological lineage analysis revealed the binding affinity of broad-spectrum substance P antagonists to receptors for gonadotropin-releasing peptide
Pharmacological lineage analysis revealed the binding affinity of broad-spectrum substance P antagonists to receptors for gonadotropin-releasing peptide
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药理学谱系分析揭示了广谱 P 物质拮抗剂与促性腺激素释放肽受体的结合亲和力
DOI：
10.1016/j.ejphar.2015.01.001
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发表时间：
2015
期刊：
影响因子：
5
通讯作者：
Koshimizu TA3
中科院分区：
文献类型：
--
作者：
Arai K;Kashiwazaki A;Fujiwara Y;Tsuchiya H;Sakai N;Shibata K;Koshimizu TA3
一组合成的P物质（SP）拮抗剂，如[Arg6， d - trp7,9，NMePhe8]- P物质（6-11）和[D-Arg1，D-Phe5, d - trp7,9，Leu11]- P物质，与一系列不同的g蛋白偶联受体（GPCR）家族成员结合，包括v1avas加压素受体，它们竞争性地抑制激动剂的结合。这种扩展的可访问性使我们能够识别具有部分保守结合位点结构的GPCR亚群。通过结合药理学数据和氨基酸序列同源矩阵，构建了对这两种SP拮抗剂敏感的gpcr的药理学谱系。我们发现对SP拮抗剂的敏感性并不局限于gq蛋白偶联的v1a和v1b受体；与Gq和Gi偶联的gs偶联v2受体和催产素受体也表现出敏感性。出乎意料的是，基于222个已知gpcr的氨基酸序列的树突图显示，一组对SP拮抗剂敏感的受体位于加压素/催产素受体附近。位于树突图中抗利尿激素受体附近的促性腺激素释放肽受体也对SP类似物敏感，而位于远离抗利尿激素受体的α 1badren能受体则不敏感。我们的发现表明，药理学谱系分析在选择包含具有广谱结合能力的配体的保守结合位点的候选受体亚群时是有用的。两种广谱SP类似物的结合位点与不同肽激动剂的结合位点部分重叠，这一知识对于理解肽配体的特异性/广泛性是有价值的。
A group of synthetic substance P (SP) antagonists, such as [Arg6,D-Trp7,9,NMePhe8]-substance P(6-11) and [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P, bind to a range of distinct G-protein-coupled receptor (GPCR) family members, including V1avasopressin receptors, and they competitively inhibit agonist binding. This extended accessibility enabled us to identify a GPCR subset with a partially conserved binding site structure. By combining pharmacological data and amino acid sequence homology matrices, a pharmacological lineage of GPCRs that are sensitive to these two SP antagonists was constructed. We found that sensitivity to the SP antagonists was not limited to the Gq-protein-coupled V1aand V1breceptors; Gs-coupled V2receptors and oxytocin receptors, which couple with both Gq and Gi, also demonstrated sensitivity. Unexpectedly, a dendrogram based on the amino acid sequences of 222 known GPCRs showed that a group of receptors sensitive to the SP antagonists are located in close proximity to vasopressin/oxytocin receptors. Gonadotropin-releasing peptide receptors, located near the vasopressin receptors in the dendrogram, were also sensitive to the SP analogs, whereas α1Badrenergic receptors, located more distantly from the vasopressin receptors, were not sensitive. Our finding suggests that pharmacological lineage analysis is useful in selecting subsets of candidate receptors that contain a conserved binding site for a ligand with broad-spectrum binding abilities. The knowledge that the binding site of the two broad-spectrum SP analogs partially overlaps with that of distinct peptide agonists is valuable for understanding the specificity/broadness of peptide ligands.