8FYE

4-F, 5-MeO-PyrT-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex

Summary for 8FYE

• Entry DOI: 10.2210/pdb8fye/pdb
• EMDB information: 29571
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: gpcr signaling complex, serotonin receptor, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 151806.48

Authors

Warren, A.L.,Zilberg, G.,Capper, M.J.,Wacker, D. (deposition date: 2023-01-26, release date: 2024-05-15, Last modification date: 2024-10-23)

Primary citation

Warren, A.L.,Lankri, D.,Cunningham, M.J.,Serrano, I.C.,Parise, L.F.,Kruegel, A.C.,Duggan, P.,Zilberg, G.,Capper, M.J.,Havel, V.,Russo, S.J.,Sames, D.,Wacker, D.
Structural pharmacology and therapeutic potential of 5-methoxytryptamines.
Nature, 630:237-246, 2024

PubMed Abstract: Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT (ref. ). However, 5-HT also plays a part in the behavioural effects of tryptamine hallucinogens, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads. Although 5-HT is a validated therapeutic target, little is known about how psychedelics engage 5-HT and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT and 5-HT enable the characterization of molecular determinants of 5-HT signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT agonists. We show that a 5-HT-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.

PubMed: 38720072
DOI: 10.1038/s41586-024-07403-2

Experimental method

ELECTRON MICROSCOPY (2.85 Å)