8V6U

5HT2AR-miniGq heterotrimer in complex with a novel agonist obtained from large scale docking

Summary for 8V6U

• Entry DOI: 10.2210/pdb8v6u/pdb
• EMDB information: 42999
• Descriptor: 5-hydroxytryptamine receptor 2A, G protein alpha-subunit q (Gi2-mini-Gq chimera), Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: active state gpcr, heterotrimer, complex, serotonin, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 142472.79

Authors

Gumpper, R.H.,Wang, L.,Kapolka, N.,Skiniotis, G.,Roth, B.L. (deposition date: 2023-12-03, release date: 2024-05-29, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3 Å)