Molecular mechanism of setron-mediated inhibition of full-length 5-HT3A receptor

被引:48
作者
Basak, Sandip [1 ]
Gicheru, Yvonne [1 ]
Kapoor, Abhijeet [2 ]
Mayer, Megan L. [3 ]
Filizola, Marta [2 ]
Chakrapani, Sudha [1 ,4 ]
机构
[1] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA
[2] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA
[3] Stanford Univ, Div CryoEM & Bioimaging, SLAC Natl Accelerator Lab, SSRL, Menlo Pk, CA 94025 USA
[4] Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
BEAM-INDUCED MOTION; LIGAND RECOGNITION; BINDING-PROTEIN; GRANISETRON; ANTAGONISTS; SOFTWARE; AGONISTS; SITE; LOCALIZATION; ORIENTATION;
D O I
10.1038/s41467-019-11142-8
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Serotonin receptor (5-HT3AR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of competitive antagonists, cause functional inhibition of 5-HT3AR in the gastrointestinal tract and brainstem, acting as effective anti-emetic agents. Despite their prevalent use, the molecular mechanisms underlying setron binding and inhibition of 5-HT3AR are not fully understood. Here, we present the structure of granisetron-bound full-length 5-HT3AR solved by single-particle cryo-electron microscopy to 2.92 angstrom resolution. The reconstruction reveals the orientation of granisetron in the orthosteric site with unambiguous density for interacting sidechains. Molecular dynamics simulations and electrophysiology confirm the granisetron binding orientation and the residues central for ligand recognition. Comparison of granisetron-bound 5-HT3AR with the apo and serotonin-bound structures, reveals key insights into the mechanism underlying 5-HT3AR inhibition.
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页数:11
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