EMD-29599

Single-particle
2.62 Å
EMD-29599 Deposition: 26/01/2023
Map released: 15/05/2024
Last modified: 06/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-29599

Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex

EMD-29599

Single-particle
2.62 Å
EMD-29599 Deposition: 26/01/2023
Map released: 15/05/2024
Last modified: 06/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Escherichia coli, Homo sapiens
Sample: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex
Fitted models: 8fyx (Avg. Q-score: 0.545)

Deposition Authors: Warren AL , Zilberg G , Capper MJ , Wacker D
Structural pharmacology and therapeutic potential of 5-methoxytryptamines.
PUBMED: 38720072
DOI: doi:10.1038/s41586-024-07403-2
ISSN: 1476-4687
ASTM: NATUAS
Abstract:
Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders1-3. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT2A (ref. 4). However, 5-HT1A also plays a part in the behavioural effects of tryptamine hallucinogens5, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads6. Although 5-HT1A is a validated therapeutic target7,8, little is known about how psychedelics engage 5-HT1A 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-HT1A, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT1A and 5-HT2A enable the characterization of molecular determinants of 5-HT1A 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-HT1A agonists. We show that a 5-HT1A-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-HT1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.