VLGR1偏向性信号转导的结构基础及动态构象变化

G蛋白偶联受体是目前已知的人类基因组中最大的一类跨膜蛋白，它调控着生物体的大部分生理功能。最近的研究发现G蛋白偶联受体VLGR1在耳聋发病过程发挥着重要的作用，可能成为治疗耳聋相关疾病新的药物靶点。我们的研究发现VLGR1可以通过Gi及β-arrestin 1 两条不同的信号转导途径在听纤毛发育过程中发挥作用，但是VLGR1与他们结合过程中构象变化机制及相互作用的结构基础却是未知的，因此本研究拟利用19F-NMR及冷冻电镜技术，研究VLGR1与不同的下游信号转导分子结合过程中的动态构象变化机制及结构基础，为深入理解GPCR的偏向性信号转导机制及靶向偏向性信号途径的药物开发提供依据。

G protein-coupled receptors (GPCRs) comprise the largest known membrane protein family encoded by the human genome, and regulate most physiologic processes in humans. Recent studies have found that G protein-coupled receptor VLGR1 plays an important role in the pathogenesis of hearing loss and is expected to the new drug target for the treatment of deafness-related diseases. Our previous work has revealed that VLGR1 contributes to the development of auditory cilia through Gi and beta-arrestin-1 signaling pathways, but the conformational change and the structural basis of their interaction remain unknown. In this study, we plan to use fluorine-19 nuclear magnetic resonance spectroscopy (19F-NMR) and cryo-electron microscopy (Cryo-EM) to investigate the structural basis and its dynamic conformation change between VLGR1 and different downstream signal transducers. Our studies will pave the way for further understanding the biased signal transduction mechanism of GPCRs and advance in biased drug discovery.