Structural basis of class C metabotropic glutamate receptor 5 signal transduction

Metabotropic glutamate receptors (mGluR) are Class C GPCRs. They are obligate dimers, dimerization being fundamental for their function. mGluRs are activated by the binding of the main excitatory neurotransmitter glutamate, within an extracellular domain (ECD). Conformational changes induced by glutamate-binding are then transmitted to the transmembrane domain composed of 7 transmembrane helices (7TM) that allows signal transduction within the cell. Class C GPCR activity can be modulated by the binding of Positive Allosteric Modulators (PAM) or Negative Allosteric Modulators (NAM) to the 7TM. Our research interest is to understand the structural basis of class C GPCR dimers signal transduction and their allosteric regulation. Multiple structures of PAM bound receptor will be solved and they will provide a comprehensive understanding on the nature of ligand binding in the 7TM as well as conformational changes associated to the binding of PAM at the mGlu receptor.

代谢型谷氨酸受体（metabotropic glutamate receptors, mGluR）属于C类G蛋白偶联受体（G protein-coupled receptor, GPCR）。该类受体为必需二聚体，二聚化是其发挥功能的核心基础。代谢型谷氨酸受体可通过胞外结构域（extracellular domain, ECD）结合机体内主要的兴奋性神经递质谷氨酸而被激活。谷氨酸结合所诱导的构象变化随后会传递至由7个跨膜螺旋（7 transmembrane helices, 7TM）组成的跨膜结构域，进而实现细胞内的信号转导。C类G蛋白偶联受体的活性可通过正向别构调节剂（Positive Allosteric Modulators, PAM）或负向别构调节剂（Negative Allosteric Modulators, NAM）结合至7TM结构域来实现调控。本研究的核心研究方向在于解析C类G蛋白偶联受体二聚体的信号转导结构基础及其别构调控机制。我们将解析多个结合了正向别构调节剂的受体结构，这些结构将帮助我们全面理解配体在7TM结构域中的结合本质，以及代谢型谷氨酸受体结合正向别构调节剂时所伴随的构象变化。