GPCR Network

GPCR网络

• 批准号: 9056148
• 负责人: RAYMOND C STEVENS
• 金额: $ 166.97万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056148
• 关键词: GPCR; Network

G protein-coupled receptors sense an astonishing variety of extracellular molecular signals and trigger complex intracellular and physiological responses. They share a common architecture of seven transmembrane helices connected by a broad range of intra- and extra-cellular loops and terminal domains. Structure determination feasibility of this protein family was demonstrated recently with the first high resolution studies on the human Beta2 adrenergic, turkey Beta1 adrenergic, and human adenosine A2A receptors. The Center for Membrane Protein Structure Determination (CMPD) has been created to use a protein family specific platform to determine the high resolution structures of 15-20 representative GPCRs distributed across the phylogenetic tree. Receptor structures are needed at a biologically relevant granularity, for small molecule ligand receptors, peptide and protein receptors, lipid receptors, class B-F receptors, and of receptors in the active and inactive functional states. Each receptor structure will be determined with a set of different pharmacological ligands to define the receptor binding site(s). Solution studies will be conducted with purified receptors bound to different ligands to understand receptor dynamics using hydrogen-deuterium exchange and NMR spectroscopy. In collaboration with the NIH screening center, a library of small molecule probes will be used to analyze each receptor and discover allosteric binding sites using a high throughput thermal stability screen. Through a biologically informed selection of representative receptors, we will maximize the CMPD's impact through computational modeling of close homolog's and functional studies by external collaborators thereby establishing The PSI GPCR Network. The generated data will be provided to the community in a time frame consistent with the guidelines of the Protein Structure Initiative. Technology access will be achieved through on-site training, workshops, meetings, and publications. Processing access to the CMPD core facility will be provided through a 30% pipeline capacity commitment for the PSI: Biology Network nominated targets. Based on the experience of the CMPD investigators, preference will be for human or eukaryotic membrane proteins to maximally leverage the CMPD capabilities.

G 蛋白偶联受体可感知种类繁多的细胞外分子信号并触发复杂的细胞内和生理反应。它们具有共同的结构，由七个跨膜螺旋组成，通过广泛的细胞内和细胞外环和末端域连接。最近，通过对人 Beta2 肾上腺素能、火鸡 Beta1 肾上腺素能和人腺苷 A2A 受体的首次高分辨率研究，证明了该蛋白质家族结构测定的可行性。膜蛋白结构测定中心 (CMPD) 的创建是为了使用蛋白质家族特定平台来确定分布在系统发育树上的 15-20 个代表性 GPCR 的高分辨率结构。对于小分子配体受体、肽和蛋白质受体、脂质受体、B-F类受体以及处于活性和非活性功能状态的受体，需要具有生物学相关粒度的受体结构。每个受体结构将通过一组不同的药理学配体来确定，以定义受体结合位点。将使用与不同配体结合的纯化受体进行溶液研究，以使用氢-氘交换和核磁共振波谱来了解受体动力学。与 NIH 筛选中心合作，小分子探针库将用于分析每种受体，并通过高通量热稳定性筛选发现变构结合位点。通过对代表性受体进行生物学选择，我们将通过外部合作者对密切同源物的计算模型和功能研究来最大化 CMPD 的影响，从而建立 PSI GPCR 网络。生成的数据将在符合蛋白质结构倡议指南的时间范围内提供给社区。技术获取将通过现场培训、研讨会、会议和出版物来实现。 CMPD 核心设施的处理访问将通过 PSI：生物网络提名目标的 30% 管道容量承诺提供。根据 CMPD 研究人员的经验，优先考虑人类或真核膜蛋白，以最大程度地利用 CMPD 功能。

项目成果

Structure of the human P2Y12 receptor in complex with an antithrombotic drug.

人类 P2Y12 受体与抗血栓药物复合物的结构。

• 发表时间: 2014-05-01
• 影响因子: 64.8
• 作者: Zhang, Kaihua;Zhang, Jin;Gao, Zhan;Zhang, Dandan;Zhu, Lan;Han, Gye Won;Moss, Steven M;Paoletta, Silvia;Kiselev, Evgeny;Lu, Weizhen;Fenalti, Gustavo;Zhang, Wenru;Müller, Christa E;Yang, Huaiyu;Jiang, Hualiang;Cherezov, Vadim;Katritch, V
• 通讯作者: Katritch, V

Preparation and Delivery of Protein Microcrystals in Lipidic Cubic Phase for Serial Femtosecond Crystallography.

用于连续飞秒晶体学的脂质立方相蛋白质微晶体的制备和递送。

• 发表时间: 2016-09-20
• 作者: Ishchenko, Andrii;Cherezov, Vadim;Liu, Wei
• 通讯作者: Liu, Wei

Allosteric Coupling of Drug Binding and Intracellular Signaling in the A 2 A Adenosine Receptor Graphical Abstract Highlights

A 2 A 腺苷受体中药物结合和细胞内信号传导的变构偶联图形摘要亮点

• 发表时间: 2024-09-14
• 作者: M. Eddy;Ming;Zhang;K. White;T. Didenko;R. Horst;Martin Audet;P. Stańczak;K. McClary;G. Han;K. Jacobson;R. Stevens;K. Wüthrich
• 通讯作者: K. Wüthrich

Serial femtosecond crystallography datasets from G protein-coupled receptors

G 蛋白偶联受体的串行飞秒晶体学数据集

• DOI: 10.1111/tbed.13107
• 发表时间: 2024-09-13
• 期刊: Transboundary and Emerging Diseases
• 影响因子: 4.3
• 作者: T. White;A. Barty;Wei Liu;A. Ishchenko;Haitao Zhang;C. Gati;N. Zatsepin;S. Basu;D. Oberthür;M. Metz;K. Beyerlein;C. Yoon;O. Yefanov;Daniel James;Dingjie Wang;M. Messerschmidt;J. Koglin;S. Boutet;U. Weierstall;V. Cherezov
• 通讯作者: V. Cherezov

Optimization of adenosine 5'-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment screening.

• DOI: 10.1021/jm300095s
• 发表时间: 2012-05-10
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Tosh, Dilip K.;Phan, Khai;Gao, Zhan-Guo;Gakh, Andrei A.;Xu, Fei;Deflorian, Francesca;Abagyan, Ruben;Stevens, Raymond C.;Jacobson, Kenneth A.;Katritch, Vsevolod
• 通讯作者: Katritch, Vsevolod