题 目：Structure insight into GPCR ligand selectivity and GPCR – G protein complex formation
主持人：袁 凯 教授
时 间：2018年11月23日（星期五）上午 10:00
刘翔宇， 2011年于北京大学获博士学位，2008-2010年攻读博士期间在丹麦Aarhus大学联合培养，2011-2013年在北京大学生命科学院从事博士后工作，2013-2017年在清华大学医学院结构生物学家Brian Kobilka课题组从事博士后及助理研究员工作。目前以共同第一或共同通讯作者在Cell、PNAS、Nature、 Nature Structural & Molecular Biology、 Nature Protocol等国际权威杂志上发表SCI论文11篇。
Abstract：GPCRs are a group of membrane receptors with seven transmembrane helices. They sense various signals from outside of the cells, transfer the signals to intracellular pathways and modulate cellular responses to environment. The ligands of GPCRs include odorants, hormones, neurotransmitters, chemokines, et al. GPCRs are targets of approximately 30% commercially available medicines. However, efforts on GPCR drug development often encounter problems with poor subtype selectivity. Because many pharmaceutically important GPCRs have different subtypes in human, and they share high homology in the orthosteric pocket, for example the nine adrenergic receptors and the five muscarinic receptors. In the first part of my presentation, I will report several crystal structures of GPCRs in complex with subtype specific ligands, including both orthosteric ligands and allosteric ligands. The structures provide guidance to GPCR drug development.
The crystal structure of beta2 adrenergic receptor (β2AR) – Gs complex provided the first high-resolution snapshot of how agonist bound GPCR activates a heterotrimeric G protein. In this nucleotide-free complex (R*-Gempty), the C-terminal alpha-5 helix of Gas undergoes a large structural change to penetrate the core of the β2AR, into a space created by the outward movement of TM6. Evidences from several sources suggest the existence of a transient complex between the β2AR and GDP bound Gs protein (β2AR-GsGDP) that may represent an intermediate on the way to the formation of β2AR-Gsempty. In the second part of my presentation, I will report a structure of the β2AR in complex with the carboxyl terminal 14 amino acids from Gαs. Together with the structure of GDP-bound Gs heterotrimer, the structures provide evidence for an alternate interaction between the β2AR and Gs that may represent an intermediate state.