Structural biology of G protein-coupled receptors

摘要 G蛋白偶联受体是人类最大的膜蛋白超家族 基因组，有800多个独特的序列。GPCR介导的信号通路在急性淋巴细胞白血病中起着关键作用 生理系统以及许多病理生理条件，因此代表着重要的药物 目标。GPCRs具有七跨膜螺旋(7TM)拓扑结构，并包含多个结合位点 正构体配体和变构调节剂。一旦识别了它们的天然配体，受体就传递信号 穿过细胞膜，到达细胞内的伙伴蛋白，如G蛋白或β-arrestins。开发一个 详细了解GPCRs的作用机制，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， 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项综合研究计划，将 结构-功能综合研究的技术开发侧重于GPCR超家族。这个 提出了加快膜高分辨结构测定的研究方向 蛋白质，提高我们对GPCR超家族的理解，并回答关于配基特异性的具体问题 和选择性，以及使用几个特定受体作为靶点的分子作用机制。我们的 方法将新受体和复合体的结构信息与从生物物理获得的数据相结合， 通过基于计算机的分析和建模进行生化和机能实验。的长期目标是 我们的实验室是为了更深入地了解GPCRs的分子作用机制 结构生物学的工具，并利用所取得的见解来加速新颖的设计和开发 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.