Crystal Structure of an LSD-Bound Human Serotonin Receptor

Daniel Wacker; Sheng Wang; John D McCorvy; Robin M Betz; A J Venkatakrishnan; Anat Levit; Katherine Lansu; Zachary L Schools; Tao Che; David E Nichols; Brian K Shoichet; Ron O Dror; Bryan L Roth

doi:10.1016/j.cell.2016.12.033

Crystal Structure of an LSD-Bound Human Serotonin Receptor

Cell. 2017 Jan 26;168(3):377-389.e12. doi: 10.1016/j.cell.2016.12.033.

Authors

Affiliations

¹ 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.
² Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
³ 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.
⁴ 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.
⁵ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158-2280, USA.
⁶ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
⁷ 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.
⁸ 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.

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-HT_2B. 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-HT_2BR and 5-HT_2AR-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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Arrestin / chemistry
Crystallography, X-Ray
Humans
Kinetics
Lysergic Acid Diethylamide / chemistry*
Models, Chemical
Molecular Dynamics Simulation
Receptor, Serotonin, 5-HT2B / chemistry*

Substances

Arrestin
Receptor, Serotonin, 5-HT2B
Lysergic Acid Diethylamide

Abstract

Publication types

MeSH terms

Substances

Grants and funding