上海科技大学iHuman研究所执行所长、中国生物物理学会副理事长、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：7月23日 上午9：00
报告地点：科学园2E 411室
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” 和“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、基金委重点和面上等项目；现任中国生物物理学会副理事长、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Cell、Nature、Immunity、Nat Stru MoleBiol、Cell Research、PNAS等SCI期刊发表研究论文100余篇；于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.
