8TRC
mGluR3 in the presence of the antagonist LY 341495 and positive allosteric modulator VU6023326
8TRC の概要
エントリーDOI | 10.2210/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 | |
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: 37645747DOI: 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) |
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