Molecular mechanism of dimeric G protein-coupled receptor signaling

摘要 我们的研究试图揭示两种蛋白的激活和调节的分子机制 二聚体G蛋白偶联受体、人GABAB受体与人钙敏感 (CAS)受体。GABAB受体在中枢神经系统中普遍存在，负责 调节缓慢和长时间的突触抑制。GABAB受体缺陷被认为与 大脑和行为障碍，包括痉挛、癫痫、成瘾和焦虑。CAS受体 维持血液中稳定的钙水平。血管紧张素转换酶受体异常活动与 钙稳态紊乱的可变性，包括潜在威胁生命的高钙血症。 这两种受体的功能都是必需的二聚体，并含有大的胞外结构域，这些结构域是 负责立体配基的结合。基本问题仍然存在，即如何 细胞外刺激通过这样的二聚体GPCR系统在膜上传播信号。 基于我们对每个受体胞外区域的结构模型，我们计划确定 这些GPCRs的全长结构，包括它们的跨膜结构域，在多种功能中 各州。对于每个受体，我们的目标是解决三个主要问题：(1)二聚体如何相互作用 控制受体激活，(2)每个受体与其认知G之间的耦合方式是什么 蛋白质是，以及(3)变构调节剂和辅助蛋白质如何调节受体功能。我们会 结合结构和功能的方法来理解配体诱导的分子基础 在每个受体系统中的激活。我们的发现将最终导致小说的发展 治疗与GABAB和cas受体相关的疾病的治疗学。

Summary Our research seeks to uncover the molecular mechanisms of activation and modulation of two dimeric G protein-coupled receptors (GPCRs), human GABAB receptor and human calcium-sensing (CaS) receptor. The GABAB receptor is ubiquitous in the central nervous system, responsible for mediating slow and prolonged synaptic inhibition. Defects in GABAB receptor have been implicated in brain and behavioral disorders, including spasticity, epilepsy, addiction, and anxiety. CaS receptor maintains a stable Ca2+ level in the blood. Abnormal activities of the CaS receptor are associated with a vareity of Ca2+ homeostatic disorders including potentially life threatening hypercalcemic conditions. Both receptors function as obligatory dimers and contain large extracellular domains that are responsible for orthosteric ligand binding. Fundamental questions remain regarding how an extracellular stimulus propagates a signal across the membrane through such a dimeric GPCR system. Building on our structural models for the extracellular domains of each receptor, we plan to determine full-length structures of these GPCRs, including their transmembrane domains, in multiple functional states. For each receptor, we aim to address three main questions: (1) how the dimeric interactions control receptor activation, (2) what the mode of coupling between each receptor and its cognitive G protein is, and (3) how allosteric modulators and auxiliary proteins regulate receptor function. We will combine structural and functional approaches to understand the molecular basis of ligand-induced activation in each receptor system. Our findings will ultimately lead to the development of novel therapeutics for treating diseases associated with the GABAB and CaS receptors.