9AS9

Local refinement of 5-HT2AR bound to RS130-180 in complex with a mini-Gq protein and scFv16 obtained by cryo-electron microscopy (cryoEM)

This is a non-PDB format compatible entry.

Summary for 9AS9

• Entry DOI: 10.2210/pdb9as9/pdb
• EMDB information: 43809
• Descriptor: 5-hydroxytryptamine receptor 2A, 2,5-dimethoxy-N,N-dimethyl-4-{2-[({2-[(prop-2-yn-1-yl)oxy]phenyl}methyl)amino]ethyl}aniline (2 entities in total)
• Functional Keywords: gpcr, g-protein coupled receptor, 5-ht2ar, serotonin, psychedelics, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 53017.41

Authors

Gumpper, R.H.,Fay, J.F.,Roth, B.L. (deposition date: 2024-02-24, release date: 2025-04-02, Last modification date: 2025-05-28)

Primary citation

Gumpper, R.H.,Jain, M.K.,Kim, K.,Sun, R.,Sun, N.,Xu, Z.,DiBerto, J.F.,Krumm, B.E.,Kapolka, N.J.,Kaniskan, H.U.,Nichols, D.E.,Jin, J.,Fay, J.F.,Roth, B.L.
The structural diversity of psychedelic drug actions revealed.
Nat Commun, 16:2734-2734, 2025

PubMed Abstract: There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A biological target of these compounds, and a hypothesized target for their therapeutic actions, is the 5-HT serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound RS130-180. Identifying the molecular interactions between various psychedelics and the 5-HT receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side effects.

PubMed: 40108183
DOI: 10.1038/s41467-025-57956-7

Experimental method

ELECTRON MICROSCOPY (3.47 Å)