8UWL

5-HT2AR bound to Lisuride in complex with a mini-Gq protein and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM)

8UWL の概要

• エントリーDOI: 10.2210/pdb8uwl/pdb
• EMDBエントリー: 42676
• 分子名称: 5-hydroxytryptamine receptor 2A, G protein subunit q (Gi2-mini-Gq chimera), Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• 機能のキーワード: 5-ht2a receptor, serotonin receptor, g protein, gpcr, lisuride, cryoem, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 142527.87

構造登録者

Barros-Alvarez, X.,Kim, K.,Panova, O.,Roth, B.L.,Skiniotis, G. (登録日: 2023-11-06, 公開日: 2024-05-29, 最終更新日: 2024-07-03)

主引用文献

Lyu, J.,Kapolka, N.,Gumpper, R.,Alon, A.,Wang, L.,Jain, M.K.,Barros-Alvarez, X.,Sakamoto, K.,Kim, Y.,DiBerto, J.,Kim, K.,Glenn, I.S.,Tummino, T.A.,Huang, S.,Irwin, J.J.,Tarkhanova, O.O.,Moroz, Y.,Skiniotis, G.,Kruse, A.C.,Shoichet, B.K.,Roth, B.L.
AlphaFold2 structures guide prospective ligand discovery.
Science, 384:eadn6354-eadn6354, 2024

PubMed Abstract: AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the σ and serotonin 2A (5-HT2A) receptors, testing hundreds of new molecules and comparing results with those obtained from docking against the experimental structures. Hit rates were high and similar for the experimental and AF2 structures, as were affinities. Success in docking against the AF2 models was achieved despite differences between orthosteric residue conformations in the AF2 models and the experimental structures. Determination of the cryo-electron microscopy structure for one of the more potent 5-HT2A ligands from the AF2 docking revealed residue accommodations that resembled the AF2 prediction. AF2 models may sample conformations that differ from experimental structures but remain low energy and relevant for ligand discovery, extending the domain of structure-based drug design.

PubMed: 38753765
DOI: 10.1126/science.adn6354

実験手法

ELECTRON MICROSCOPY (2.8 Å)