Molecular mechanism of dimeric G protein-coupled receptor signaling

总结 我们的研究旨在揭示激活和调节两种蛋白质的分子机制。 二聚G蛋白偶联受体（GPCR）、人GABAB受体和人钙敏感 (CaS)受体的GABAB受体在中枢神经系统中普遍存在，负责 介导缓慢且延长的突触抑制。GABAB受体的缺陷与 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Ca2+水平。CaS受体的异常活动与 Ca2+稳态紊乱的多样性，包括可能危及生命的高钙血症。 这两种受体作为专性二聚体发挥功能，并含有大的胞外结构域， 负责正构配体结合。基本问题仍然存在， 细胞外刺激通过这种二聚GPCR系统跨膜传播信号。 基于我们对每个受体胞外结构域的结构模型，我们计划确定 这些GPCR的全长结构，包括它们的跨膜结构域，在多个功能中， states.对于每个受体，我们的目标是解决三个主要问题：（1）二聚体相互作用如何 控制受体激活，（2）每个受体与其认知G 蛋白质是什么，以及（3）变构调节剂和辅助蛋白质如何调节受体功能。我们将 联合收割机的结构和功能的方法来了解配体诱导的分子基础， 激活每个受体系统。我们的发现将最终导致小说的发展 用于治疗与GABAB和CaS受体相关的疾病的治疗剂。

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.