9WPX

5-HT2AR bound to IHCH-1904 in complex with mini-Gq and scFv16 obtained by cryo-electron microscopy (cryoEM)

This is a non-PDB format compatible entry.

Summary for 9WPX

• Entry DOI: 10.2210/pdb9wpx/pdb
• EMDB information: 66152
• Descriptor: 5-hydroxytryptamine receptor 2A, G protein subunit q (Gi2-mini-Gq chimera), Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, serotonin receptor, membrane protein, 5-ht2ar, signaling protein/immune system, signaling protein-immune system complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 142414.76

Authors

Li, H.,Tang, L.,Zhang, J.,Meng, B.,Cao, D.,Chen, Y.,Yu, J.,Liu, Z.,Wang, S.,Cheng, J. (deposition date: 2025-09-10, release date: 2026-09-16, Last modification date: 2026-09-30)

Primary citation

Li, H.,Tang, L.,Zhang, J.,Meng, B.,Cao, D.,Chen, Y.,Yu, J.,Wang, H.,Liu, Z.J.,Wang, S.,Cheng, J.
Structure-based design of subtype-selective psychedelic analogs.
Nat Commun, 17:-, 2026

PubMed Abstract: Classical psychedelics exert hallucinogenic and therapeutic effects primarily through activation of serotonin 2 A receptor (5-HTR), offering promise as transformative treatments for neuropsychiatric disorders. However, their concurrent activation of 5-HTR-associated with cardiac valvulopathy-raises serious safety concerns, underscoring the need for subtype-selective psychedelics. To address this, we determine the cryo-EM structure of 5-HTR and perform a comparative structural analysis of the orthosteric binding pockets (OBPs) of 5-HTR and 5-HTR. Guided by key residue differences, we develop a trigonal pharmacophore model to inform the design of 5-HTR-selective agonists that avoid 5-HTR activation. Using this model, we design and synthesize two compound series that selectively activate 5-HTR while antagonizing 5-HTR. Molecular basis of subtype selectivity is confirmed by five additional cryo-EM structures of receptor-ligand complexes. Selected compounds also exhibit antidepressant-like efficacy in animal models. Our findings provide a strategy for the development of safer, subtype-selective psychedelic analogs with therapeutic potential.

PubMed: 42754591
DOI: 10.1038/s41467-026-77658-y

Experimental method

ELECTRON MICROSCOPY (3.1 Å)