22WP

local reifnement of 5HT2AR-miniGq heterotrimer in complex with a psychedelic psilocin

Summary for 22WP

• Entry DOI: 10.2210/pdb22wp/pdb
• EMDB information: 68735
• Descriptor: 5-hydroxytryptamine receptor 2A, 3-[2-(dimethylamino)ethyl]-1~{H}-indol-4-ol (2 entities in total)
• Functional Keywords: gpcr, serotonin receptor, membrane protein, 5ht2ar
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 37711.54

Authors

Tang, L.,Ji, X.,Cheng, J.,Wang, S. (deposition date: 2026-01-26, release date: 2026-09-16, Last modification date: 2026-09-30)

Primary citation

Tang, L.,Ji, X.,Wang, Y.,Cao, D.,Li, H.,He, L.,Cheng, J.,Wang, S.
Mechanistic Basis for 5-HT 2A R Over 5-HT 2B R Activation.
Nat Commun, 17:-, 2026

PubMed Abstract: Selective 5-HTR agonism without 5-HTR activation is critical for safe psychedelic-inspired therapeutics. Here, we systematically probe the ligand-binding pockets of 5-HTR and 5-HTR and identify steric and conformational constraints at the side-extended pocket (SEP) and extended binding pocket (EBP) that dictate ligand orientation and receptor signaling. Guided by these insights, we design derivatives across tryptamine and phenethylamine scaffolds that integrate SEP and EBP engagement with scaffold modification to reinforce 5-HTR activation while limiting 5-HTR activity. Cryo-EM structures of 5-HTR and 5-HTR bound to IHCH-2330, a selective 5-HTR agonist and 5-HTR antagonist, confirm the design principle. These findings show differential activation mechanisms between 5-HTR and 5-HTR and provide a rational framework for engineering safer, functionally selective serotonergic compounds, mitigating 5-HTR-mediated side effects while preserving therapeutic efficacy.

PubMed: 42754589
DOI: 10.1038/s41467-026-77659-x

Experimental method

ELECTRON MICROSCOPY (3.33 Å)