8WG9

mGlu2-mGlu4 heterodimer bound mGlu4 agonist E7P

8WG9 の概要

• エントリーDOI: 10.2210/pdb8wg9/pdb
• EMDBエントリー: 37506
• 分子名称: Metabotropic glutamate receptor 4, Metabotropic glutamate receptor 2, (2S)-2-amino-4-phosphonobutanoic acid (3 entities in total)
• 機能のキーワード: gpcr, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 192409.79

構造登録者

Zhang, Y.,Liu, J. (登録日: 2023-09-20, 公開日: 2024-11-27, 最終更新日: 2025-05-28)

主引用文献

Huang, W.,Jin, N.,Guo, J.,Shen, C.,Xu, C.,Xi, K.,Bonhomme, L.,Quast, R.B.,Shen, D.D.,Qin, J.,Liu, Y.R.,Song, Y.,Gao, Y.,Margeat, E.,Rondard, P.,Pin, J.P.,Zhang, Y.,Liu, J.
Structural basis of orientated asymmetry in a mGlu heterodimer.
Nat Commun, 15:10345-10345, 2024

PubMed Abstract: The structural basis for the allosteric interactions within G protein-coupled receptors (GPCRs) heterodimers remains largely unknown. The metabotropic glutamate (mGlu) receptors are complex dimeric GPCRs important for the fine tuning of many synapses. Heterodimeric mGlu receptors with specific allosteric properties have been identified in the brain. Here we report four cryo-electron microscopy structures of mGlu2-4 heterodimer in different states: an inactive state bound to antagonists, two intermediate states bound to either mGlu2 or mGlu4 agonist only and an active state bound to both glutamate and a mGlu4 positive allosteric modulator (PAM) in complex with Gi protein. In addition to revealing a unique PAM binding pocket among mGlu receptors, our data bring important information for the asymmetric activation of mGlu heterodimers. First, we show that agonist binding to a single subunit in the extracellular domain is not sufficient to stabilize an active dimer conformation. Single-molecule FRET data show that the monoliganded mGlu2-4 can be found in both intermediate states and an active one. Second, we provide a detailed view of the asymmetric interface in seven-transmembrane (7TM) domains and identified key residues within the mGlu2 7TM that limits its activation leaving mGlu4 as the only subunit activating G proteins.

PubMed: 39609406
DOI: 10.1038/s41467-024-54744-7

実験手法

ELECTRON MICROSCOPY (4.46 Å)