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8TRC

mGluR3 in the presence of the antagonist LY 341495 and positive allosteric modulator VU6023326

8TRC の概要
エントリーDOI10.2210/pdb8trc/pdb
EMDBエントリー41577
分子名称Metabotropic glutamate receptor 3, 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine (2 entities in total)
機能のキーワードgpcr, synaptic protein, membrane protein
由来する生物種Rattus norvegicus (Norway rat)
タンパク質・核酸の鎖数2
化学式量合計207029.85
構造登録者
Strauss, A.,Levitz, J. (登録日: 2023-08-09, 公開日: 2024-07-31, 最終更新日: 2024-10-16)
主引用文献Strauss, A.,Gonzalez-Hernandez, A.J.,Lee, J.,Abreu, N.,Selvakumar, P.,Salas-Estrada, L.,Kristt, M.,Marx, D.C.,Gilliland, K.,Melancon, B.J.,Filizola, M.,Meyerson, J.,Levitz, J.
Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization.
Biorxiv, 2023
Cited by
PubMed Abstract: The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted either at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric TMD-targeting compounds as therapeutics, an understanding of the functional and structural basis of their effects on mGluRs is limited. Here we use a battery of approaches to dissect the distinct functional and structural effects of orthosteric versus allosteric ligands. We find using electrophysiological and live cell imaging assays that both agonists and positive allosteric modulators (PAMs) can drive activation and desensitization of mGluRs. The effects of PAMs are pleiotropic, including both the ability to boost the maximal response to orthosteric agonists and to serve independently as desensitization-biased agonists across mGluR subtypes. Conformational sensors reveal PAM-driven inter-subunit re-arrangements at both the LBD and TMD. Motivated by this, we determine cryo-electron microscopy structures of mGluR3 in the presence of either an agonist or antagonist alone or in combination with a PAM. These structures reveal PAM-driven re-shaping of intra- and inter-subunit conformations and provide evidence for a rolling TMD dimer interface activation pathway that controls G protein and beta-arrestin coupling.
PubMed: 37645747
DOI: 10.1101/2023.08.13.552748
主引用文献が同じPDBエントリー
実験手法
ELECTRON MICROSCOPY (3.3 Å)
構造検証レポート
Validation report summary of 8trc
検証レポート(詳細版)ダウンロードをダウンロード

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件を2025-07-02に公開中

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