Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD

Cao, Can; Barros-Álvarez, Ximena; Zhang, Shicheng; Kim, Kuglae; Dämgen, Marc A.; Panova, Ouliana; Suomivuori, Carl-Mikael; Fay, Jonathan F.; Zhong, Xiaofang; Krumm, Brian E.; Gumpper, Ryan H.; Seven, Alpay B.; Robertson, Michael J.; Krogan, Nevan J.; Hüttenhain, Ruth; Nichols, David E.; Dror, Ron O.; Skiniotis, Georgios; Roth, Bryan L.

doi:10.1016/j.neuron.2022.08.006

Title: Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD

Journal Article · 09 September 2022 · Neuron

DOI: https://doi.org/10.1016/j.neuron.2022.08.006 · OSTI ID:2424034

Cao, Can ^[1]; Barros-Álvarez, Ximena ^[2]; Zhang, Shicheng ^[1]; Kim, Kuglae ^[3]; Dämgen, Marc A. ^[2]; Panova, Ouliana ^[2]; Suomivuori, Carl-Mikael ^[2]; Fay, Jonathan F. ^[1]; Zhong, Xiaofang ^[4]; Krumm, Brian E. ^[1]; Gumpper, Ryan H. ^[1]; Seven, Alpay B. ^[2]; Robertson, Michael J. ^[2]; Krogan, Nevan J. ^[4]; Hüttenhain, Ruth ^[4]; Nichols, David E. ^[1]; Dror, Ron O. ^[2]; Skiniotis, Georgios ^[2]; Roth, Bryan L. ^[1]

University of North Carolina, Chapel Hill, NC (United States)
Stanford Univ., CA (United States)
University of North Carolina, Chapel Hill, NC (United States); Yonsei Univ. (Korea, Republic of)
Univ. of California, San Francisco, CA (United States); J. David Gladstone Institutes, San Francisco, CA (United States)

Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT_2A serotonin receptor (HTR2A), the 5-HT_2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. Here, in this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD’s action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2424034

Journal Information:: Neuron, Journal Name: Neuron Journal Issue: 19 Vol. 110; ISSN 0896-6273

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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