Structural biology of G protein-coupled receptors

摘要 G蛋白偶联受体（GPCRs）是人类最大的膜蛋白超家族 基因组，有超过800个独特的序列。GPCR介导的信号传导通路在所有 生理系统以及许多病理生理条件，因此代表重要的药物 目标的GPCR具有七跨膜螺旋（7 TM）拓扑结构，并包含多个结合位点， 正构配体和变构调节剂。在识别其天然配体后，受体传递信号 穿过细胞膜到达细胞内伴侣蛋白，如G蛋白或β-抑制蛋白。开发一 详细了解GPCR的功能机制，并促进具有高活性的新药的设计 选择性和效力需要获得高分辨率的三维结构，对其的测定， 然而，这仍然是一项具有挑战性的任务。我们在这里提出了一个全面的研究计划， 技术开发与集成的结构-功能研究集中在GPCR超家族。的 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，以及使用几种特异性受体作为靶标的分子作用机制。我们 该方法将新受体和复合物的结构信息与从生物物理学， 生物化学和功能实验，通过基于计算机的分析和建模。的长期目标 我们的实验室是发展一个更深入的了解的分子机制的作用GPCR使用的 结构生物学的工具，并利用所取得的见解，以加速设计和开发新的 和有效的治疗方法。

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.