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

被引：77

作者：

Cao, Can ^{[1
]}

Barros-Alvarez, Ximena ^{[2
]}

Zhang, Shicheng ^{[1
]}

Kim, Kuglae ^{[1
,10
]}

Damgen, Marc A. ^{[2
,3
,4
]}

Panova, Ouliana ^{[2
]}

Suomivuori, Carl-Mikael ^{[2
,3
,4
]}

Fay, Jonathan F. ^{[5
]}

Zhong, Xiaofang ^{[6
,7
,8
]}

Krumm, Brian E. ^{[1
]}

Gumpper, Ryan H. ^{[1
]}

Seven, Alpay B. ^{[2
]}

Robertson, Michael J. ^{[2
]}

Krogan, Nevan J. ^{[6
,7
,8
]}

Huttenhain, Ruth ^{[6
,7
,8
]}

Nichols, David E. ^{[9
]}

Dror, Ron O. ^{[2
,3
,4
]}

Skiniotis, Georgios ^{[2
]}

Roth, Bryan L. ^{[1
,9
]}

机构：

[1] Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA

[2] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Dept Struct Biol, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA

[4] Stanford Univ, Inst Computat & Math Engn, Stanford, CA 94305 USA

[5] Univ N Carolina, Dept Biochem & Biophys, Sch Med, Chapel Hill, NC USA

[6] Univ Calif San Francisco, Quantitat Biosci Inst QBI, San Francisco, CA USA

[7] J David Gladstone Inst, San Francisco, CA USA

[8] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA USA

[9] Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA

[10] Yonsei Univ, Dept Pharm, Incheon 21983, South Korea

来源：

NEURON | 2022年 / 110卷 / 19期

关键词：

PROTEIN-COUPLED RECEPTORS; MOLECULAR-DYNAMICS; FUNCTIONAL SELECTIVITY; STRUCTURAL INSIGHTS; CRYSTAL-STRUCTURE; BETA-ARRESTIN; PHOSPHORYLATION; VALIDATION; MECHANISM; MEMBRANES;

D O I：

10.1016/j.neuron.2022.08.006

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 medi-ated by the 5-HT2A serotonin receptor (HTR2A), the 5-HT2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and sim-ilarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer -free, Gq-protein-coupled, and b-arrestin-1-coupled states. These structures provide distinct signaling snap-shots 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.

引用

页码：3154 / +

页数：22

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