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标题：Mechanism of Inverse Agonist Action of Sarpogrelate at the Constitutively Active Mutant of Human 5-HT2A Receptor Revealed by Molecular Modeling
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作者：Murad Hossain ; Habib Abul Muntasir ; Masaji Ishiguro 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2012
卷号：35
期号：9
页码：1553-1559
DOI：10.1248/bpb.b12-00401
出版社：The Pharmaceutical Society of Japan
摘要：We previously reported that sarpogrelate, a selective 5-HT_2A antagonist, showed a potent inverse agonist activity to constitutively active mutant (C322K) of human 5-HT_2A receptor (5-HT_2AR). However, it remains to be unknown about the actual mechanism of this mutant for its constitutive activation as well as inverse agonist activity of sarpogrelate. Our model shows that mutation (C322K) of 5-HT_2AR causes electronic repulsion between positively charged Arg173(3.50) and Lys322(6.34) residues resulting outward movement of the C-terminus of transmembrane helix (TMH) III. This motion of TMH III leads to a partially active structure of the receptor, which may be a key step in receptor activation. The structural model of the partially active receptor also indicates that the binding of sarpogrelate to the constitutively active receptor causes an inward swing of TMH III to an inactive receptor structure. Therefore, the present study may suggest that the electronic repulsion causing outward movement of the C-terminus of TMH III may be the key step for constitutive activation of mutant C322K of 5-HT_2AR and the inward movement of TMH III causes the inverse agonist activity of sarpogrelate.
关键词：5-HT2A receptor;mutation;constitutive activity;molecular modeling;electronic repulsion