中国科学院上海药物研究所吴蓓丽研究组报道了代谢性谷氨酸受体(mGlus)2-mGlu3和mGlu2-mGlu4异源二聚体二聚化和激活的结构见解。2023年6月8日出版的《细胞研究》发表了这项成果。

本文报道了mGlu2-mGlu3和mGlu2-mGlu4异二聚体在不同构象状态下的12个冷冻电镜结构，包括非活性构象、中间非活性构象、中间活性构象和完全活性构象。这些结构提供了mGlu2-mGlu3活化后构象重排的完整图像。捕蝇草结构域经历了连续的构象变化，而跨膜结构域则表现出从具有不同二聚化模式的非活性对称二聚体到具有保守二聚化模式的活性非对称二聚体的大量重排。

结合功能数据，这些结构揭示了亚基非活性构象的稳定性和亚基- g蛋白相互作用模式是异源二聚体不对称信号转导的决定因素。此外，在mGlu2-mGlu4异源二聚体和mGlu4同源二聚体的不对称二聚体界面上，发现了两个mGlu4正变构调节剂的新结合位点，可能作为药物识别位点。这些发现极大地扩展了人们对mGlus信号转导的认识。

据了解, mGlus的异二聚化在受体的功能调节中显示出重要作用，并为治疗中枢神经系统疾病提供了潜在的药物靶点。然而，由于缺乏mGlu异源二聚体的分子细节，对mGlu异源二聚体和激活机制的理解是有限的。

附：英文原文

Title: Structural insights into dimerization and activation of the mGlu2–mGlu3 and mGlu2–mGlu4 heterodimers

Author: Wang, Xinwei, Wang, Mu, Xu, Tuo, Feng, Ye, Shao, Qiang, Han, Shuo, Chu, Xiaojing, Xu, Yechun, Lin, Shuling, Zhao, Qiang, Wu, Beili

Issue&Volume: 2023-06-08

Abstract: Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2–mGlu3 and mGlu2–mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2–mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit–G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2–mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus.

DOI: 10.1038/s41422-023-00830-2

Source: https://www.nature.com/articles/s41422-023-00830-2