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PMID: 28129538 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Crystal Structure of an LSD-Bound Human Serotonin Receptor.

Cell ·Vol. 168 ·No. 3 ·2017-00-26 ·Pages 377-389.e12

Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, Lansu K, Schools ZL, Che T, Nichols DE, Shoichet BK, Dror RO, Roth BL

Abstract

The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. PAPERCLIP.

Keywords
GPCR crystallography hallucinogens serotonin receptor structure-function
MeSH Terms
Arrestin/chemistry Crystallography, X-Ray Humans Kinetics Lysergic Acid Diethylamide/chemistry Models, Chemical Molecular Dynamics Simulation Receptor, Serotonin, 5-HT2B/chemistry
Chemicals
Arrestin Receptor, Serotonin, 5-HT2B Lysergic Acid Diethylamide
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Wacker Daniel
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA. Electronic address: dwacker@email.unc.edu.
Wang Sheng
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
McCorvy John D
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
Betz Robin M
Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA; Biophysics Program, Stanford University, Stanford, CA 94305, USA.
Venkatakrishnan A J
Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
Levit Anat
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158-2280, USA.
Lansu Katherine
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
Schools Zachary L
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
Che Tao
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
Nichols David E
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
Shoichet Brian K
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158-2280, USA.
Dror Ron O
Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA; Biophysics Program, Stanford University, Stanford, CA 94305, USA. Electronic address: ron.dror@stanford.edu.
Roth Bryan L
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA. Electronic address: bryan_roth@med.unc.edu.
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2016.12.033
Email
dwacker@email.unc.edu
ron.dror@stanford.edu
bryan_roth@med.unc.edu
Published
2017-00-26
Pages
377-389.e12
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC5289311
Subset
IM
Grants
NIMH NIH HHS · U19 MH082441 · United States
NCI NIH HHS · P30 CA016086 · United States
NIMH NIH HHS · R01 MH099993 · United States
NIGMS NIH HHS · T32 GM007040 · United States
NIMH NIH HHS · R01 MH112205 · United States
NIGMS NIH HHS · T32 GM008294 · United States
NIMH NIH HHS · R01 MH061887 · United States
NIGMS NIH HHS · R01 GM059957 · United States
Corrections
CommentIn
PMID: 28129534
External Links
PubMed source DOI: 10.1016/j.cell.2016.12.033 PMC Full Text View journal details
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