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上海科技大学iHuman研究所执行所长刘志杰学术报告通知
Publisher:高雪  Time2018-07-19 View:140

上海科技大学iHuman研究所执行所长、中国生物物理学会理事长、上海生物物理学会副理事长、中国晶体学会理事国际生物结晶组织(IOBCr)、亚洲晶体学会、国际晶体学专业杂志IUCrJ编委国务院政府特殊津贴获得者——刘志杰教授来访我校,访问期间将举办学术报告进行交流,欢迎相关师生参加。

报告题目:Structural  Biology Study of Human Cannabinoid Receptor CB1

报告时间:723日  上午900

报告地点:科学园2E  411

主办单位:生命科学与技术学院/生命科学中心

报告人简介:

刘志杰,男,现任上海科技大学iHuman研究所教授,执行所长。曾任中国科学院生物物理研究所研究员作为首席科学家主持科技部“973”  “863”重大研究项目、卫生部艾滋病和病毒性肝炎等重大传染病防治科技重大专项、基金委重点和面上项目现任中国生物物理学会理事长、上海生物物理学会副理事长、中国晶体学会理事国际生物结晶组织(IOBCr)、亚洲晶体学会、国际晶体学专业杂志IUCrJ编委。

刘志杰教授已在CellNatureImmunityNat  Stru MoleBiolCell  ResearchPNASSCI期刊发表研究论文100余篇2012  年成为享受国务院政府特殊津贴专家,同年获药明康德生命化学研究奖。目前从事人体细胞信号转导相关蛋白的结构生物学和基于结构的药物发现研究。

报告摘要:

In  humans, GPCRs signal in response to a diverse array of stimuli including light  molecules, hormones, and lipids, where these signals affect downstream cascades  to impact both health and disease states. Yet, despite their importance as  therapeutic targets, detailed molecular structures of only ~50 unique GPCRs have  been determined to date. A key challenge to their structure determination is  adequate stable protein expression and crystallization. I’ll present the methods  and technologies for obtaining human cannabinoid receptor CB1 which  are suitable for crystallization.

I’ll  also present thecrystal  structures of human CB1 in  complex with different stabilizing ligands, designed, synthesized and  characterized for the structural studies. The structure of the antagonist bound  CB1-AM6538  complex reveals an expansive and complicated binding pocket network consisting  of multiple sub-pockets and channels to various regions of the receptor. The  three-arm ligand structure is common to CB1 antagonists  and inverse agonists and may be critical for stabilizing the inherent  flexibility of the native receptor in a non-signaling conformation. The  structures of the agonist bound CB1-AM11542  and CB1-AM841 complexes uncovered significant conformational changes in the  overall structure, relative to the antagonist-bound state1,  including a 53% reduction in volume of the ligand binding pocket and an increase  in the surface area of the G protein binding region. In addition, a “twin toggle  switch” of Phe2003.36/Trp3566.48  is  experimentally observed and appears to be essential in receptor activation. The  structures reveal important insights into the activation mechanism of  CB1 and  provide a molecular basis for predicting the binding modes of Δ9-THC,  the endogenous and synthetic cannabinoids. The plasticity of the binding pocket  of CB1 appears  to be a common feature among certain class A GPCRs. These key findings should  inspire the design of chemically diverse ligands with distinct pharmacological  properties.