8JD5

Cryo-EM structure of Gi1-bound mGlu2-mGlu4 heterodimer

8JD5 の概要

• エントリーDOI: 10.2210/pdb8jd5/pdb
• EMDBエントリー: 36176 36226 36227 36286
• 分子名称: Metabotropic glutamate receptor 2, DI-PALMITOYL-3-SN-PHOSPHATIDYLETHANOLAMINE, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (12 entities in total)
• 機能のキーワード: complex structure, gi1-bound mglu2-mglu4 heterodimer, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 316653.32

構造登録者

Wang, X.,Wang, M.,Xu, T.,Feng, Y.,Han, S.,Zhao, Q.,Wu, B. (登録日: 2023-05-12, 公開日: 2023-06-21, 最終更新日: 2024-10-16)

主引用文献

Wang, X.,Wang, M.,Xu, T.,Feng, Y.,Shao, Q.,Han, S.,Chu, X.,Xu, Y.,Lin, S.,Zhao, Q.,Wu, B.
Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers.
Cell Res., 33:762-774, 2023

PubMed 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.

PubMed: 37286794
DOI: 10.1038/s41422-023-00830-2

実験手法

ELECTRON MICROSCOPY (3.6 Å)