4.6 Article

''Network leaning as a mechanism of insurmountable antagonism of the angiotensin II type 1 receptor by non-peptide antagonists

期刊

JOURNAL OF BIOLOGICAL CHEMISTRY
卷 279, 期 15, 页码 15248-15257

出版社

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M312728200

关键词

-

资金

  1. NHLBI NIH HHS [R01 HL057470, HL57490, R01 HL064845] Funding Source: Medline

向作者/读者索取更多资源

A mechanistic understanding of the insurmountable antagonism of the angiotensin II type 1 (AT(1)) receptor could be fundamental in the quest for discovery and improvement of drugs. Candesartan and EXP3174 are competitive, reversible insurmountable antagonists of the AT(1) receptor. They contain di-acidic substitutions, whereas the surmountable antagonist, losartan, contains only one acidic group. We tested the hypothesis that these two classes of ligands interact with the AT(1) receptor through similar but not identical bonds and that the differences in the acid-base group contacts are critical for insurmountable antagonism. By pharmacological characterization of site-directed AT(1) receptor mutants expressed in COS1 cells we show that specific interactions with Gln(257) in transmembrane 6 distinguishes insurmountable antagonists and that abolishing these interactions transforms insurmountable to surmountable antagonism. In the Q257A mutant, the dissociation rate of [H-3] candesartan is 2.8-fold more than the rate observed with wild type, and the association rate was reduced 4-fold lower than the wild type. The pattern of antagonism of angiotensin II concentration-response in the Q257A mutant pretreated with EXP3174 and candesartan is surmountable. We propose that leaning ability of insurmountable antagonists on Gln(257) in the wildtype receptor is the basis of an antagonist-mediated conformational transition, which is responsible for both slow dissociation and inhibition of maximal IP response.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据