Structural biology of G protein-coupled receptors

G蛋白偶联受体的结构生物学

• 批准号: 9925243
• 负责人: Vadim Cherezov
• 金额: $ 41.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925243
• 关键词: Arrestins; Binding Sites; Biochemical; Biophysics; Cardiovascular Diseases; Cell membrane; Complex; Computers; Data; Development; Diabetes Mellitus; Drug Prescriptions; Drug Targeting; Family; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Human; Human Genome; Immune System Diseases; Laboratories; Ligands; Malignant Neoplasms; Membrane Proteins; Metabolic Diseases; Modeling; Molecular; Molecular Mechanisms of Action; Obesity; Pain; Physiological; Play; Proteins; Research; Resolution; Signal Pathway; Signal Transduction; Specificity; Structure; System; Therapeutic; Translating; addiction; base; design; experimental study; improved; insight; novel; novel therapeutics; programs; receptor; receptor function; receptor-mediated signaling; side effect; structural biology; technology development; three dimensional structure; tool

Abstract G protein-coupled receptors (GPCRs) constitute the largest membrane protein superfamily in the human genome, with over 800 unique sequences. GPCR-mediated signaling pathways play a key role in all physiological systems as well as many pathophysiological conditions, and therefore represent important drug targets. GPCRs have a seven-transmembrane-helix (7TM) topology and contain multiple binding sites for orthosteric ligands and allosteric modulators. Upon recognition of their native ligands receptors transmit signals across the cell membrane to intracellular partner proteins, such as G proteins or β-arrestins. Developing a detailed understanding of functional mechanisms of GPCRs and facilitating design of novel drugs with high selectivity and potency require access to high-resolution three-dimensional structures, determination of which, however, remains a challenging task. We propose here a comprehensive research program which combines technology development with integrated structure-function studies focused on the GPCR superfamily. The proposed research directions are designed to accelerate high-resolution structure determination of membrane proteins, improve our understanding of the GPCR superfamily and answer specific questions on ligand specificity and selectivity, as well as molecular mechanisms of action using several specific receptors as targets. Our approach integrates structural information on new receptors and complexes with data obtained from biophysical, biochemical and functional experiments through computer-based analysis and modeling. The long-term goal of our laboratory is to develop a deeper understanding of the molecular mechanisms of action of GPCRs using the tools of structural biology, and to use the achieved insights to accelerate the design and development of novel and efficacious therapeutics.

抽象的 G蛋白偶联受体（GPCR）构成了人类最大的膜蛋白超家族 基因组具有超过 800 个独特的序列，GPCR 介导的信号通路在所有这些中发挥着关键作用。 生理系统以及许多病理生理条件，因此代表重要的药物 GPCR 具有七跨膜螺旋 (7TM) 拓扑结构，并包含多个结合位点。 正构配体和变构调节剂在识别其天然配体受体后传递信号。 穿过细胞膜到达细胞内伴侣蛋白，例如 G 蛋白或 β-抑制蛋白。 详细了解GPCR的功能机制，促进高活性新药的设计 选择性和效力需要获得高分辨率的三维结构，对其进行测定， 然而，这仍然是一项具有挑战性的任务，我们在此提出一项综合研究计划。 以 GPCR 超家族为重点的集成结构功能研究的技术开发。 提出的研究方向旨在加速膜的高分辨率结构测定 蛋白质，提高我们对 GPCR 超家族的理解并回答有关配体特异性的具体问题 和选择性，以及使用几种特定受体作为靶标的分子作用机制。 该方法将新受体和复合物的结构信息与从生物物理学获得的数据相结合， 通过基于计算机的分析和建模进行生化和功能实验的长期目标。 我们的实验室旨在利用以下方法更深入地了解 GPCR 的分子作用机制： 结构生物学工具，并利用所获得的见解来加速新颖的设计和开发 和有效的治疗方法。