Structural determinants of 5-HT2B receptor activation and biased agonism | |
McCorvy, John D.1,2,5; Wacker, Daniel1,2,6,7; Wang, Sheng1,2,8; Agegnehu, Bemnat1,2; Lansu, Katherine1,2; Tribo, Alexandra R.1,2; Olsen, Reid H. J.1,2; Che, Tao1,2; Roth, Bryan L.1,2; Jin, Jian3,4 | |
刊名 | NATURE STRUCTURAL & MOLECULAR BIOLOGY |
2018 | |
卷号 | 25期号:9页码:787-+ |
关键词 | Protein-coupled Receptors Valvular Heart-disease Stabilized Active State Crystal-structure Serotonin Receptors Nanobody Drug Fenfluramine Pharmacology Ligands |
ISSN号 | 1545-9993 |
DOI | 10.1038/s41594-018-0116-7 |
文献子类 | Article |
英文摘要 | Serotonin (5-hydroxytryptamine; 5-HT) receptors modulate a variety of physiological processes ranging from perception, cognition and emotion to vascular and smooth muscle contraction, platelet aggregation, gastrointestinal function and reproduction. Drugs that interact with 5-HT receptors effectively treat diseases as diverse as migraine headaches, depression and obesity. Here we present four structures of a prototypical serotonin receptor-the human 5-HT2B receptor-in complex with chemically and pharmacologically diverse drugs, including methysergide, methylergonovine, lisuride and LY266097. A detailed analysis of these structures complemented by comprehensive interrogation of signaling illuminated key structural determinants essential for activation. Additional structure-guided mutagenesis experiments revealed binding pocket residues that were essential for agonist-mediated biased signaling and beta-arrestin2 translocation. Given the importance of 5-HT receptors for a large number of therapeutic indications, insights derived from these studies should accelerate the design of safer and more effective medications. |
电子版国际标准刊号 | 1545-9985 |
WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics ; Cell Biology |
语种 | 英语 |
WOS记录号 | WOS:000443839200008 |
内容类型 | 期刊论文 |
版本 | 出版稿 |
源URL | [http://202.127.25.143/handle/331003/3477] |
专题 | 生化所2018年发文 上海生化细胞研究所_上海生科院生化细胞研究所 |
通讯作者 | McCorvy, John D.; Roth, Bryan L. |
作者单位 | 1.Univ N Carolina, Natl Inst Mental Hlth, Psychoact Drug Screening Program, Dept Pharmacol,Med Sch, Chapel Hill, NC 27515 USA; 2.Univ N Carolina, Div Chem Biol & Med Chem, Sch Med, Chapel Hill, NC 27515 USA; 3.Icahn Sch Med Mt Sinai, Ctr Chem Biol & Drug Discovery, Dept Pharmacol Sci, New York, NY 10029 USA; 4.Icahn Sch Med Mt Sinai, Tisch Canc Inst, Dept Oncol Sci, New York, NY 10029 USA; 5.Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA; 6.Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA; 7.Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA; 8.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai, Peoples R China |
推荐引用方式 GB/T 7714 | McCorvy, John D.,Wacker, Daniel,Wang, Sheng,et al. Structural determinants of 5-HT2B receptor activation and biased agonism[J]. NATURE STRUCTURAL & MOLECULAR BIOLOGY,2018,25(9):787-+. |
APA | McCorvy, John D..,Wacker, Daniel.,Wang, Sheng.,Agegnehu, Bemnat.,Lansu, Katherine.,...&Liu, Jing.(2018).Structural determinants of 5-HT2B receptor activation and biased agonism.NATURE STRUCTURAL & MOLECULAR BIOLOGY,25(9),787-+. |
MLA | McCorvy, John D.,et al."Structural determinants of 5-HT2B receptor activation and biased agonism".NATURE STRUCTURAL & MOLECULAR BIOLOGY 25.9(2018):787-+. |
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