title: Crystal Structure of an LSD-Bound Human Serotonin Receptor.
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.
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wacker
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: McCorvy
authors.affiliation: 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.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Betz
authors.affiliation: 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.
authors.forename: A J
authors.initials: AJ
authors.lastname: Venkatakrishnan
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158-2280, USA.
authors.forename: Anat
authors.initials: A
authors.lastname: Levit
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Lansu
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Schools
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Che
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158-2280, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.affiliation: 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.
authors.forename: Ron O
authors.initials: RO
authors.lastname: Dror
authors.affiliation: 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.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D019393:Arrestin / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008238:Lysergic Acid Diethylamide / Q000737:chemistry*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry*
chemical_list: D019393:Arrestin; D044403:Receptor, Serotonin, 5-HT2B; D008238:Lysergic Acid Diethylamide
keywords: GPCR; crystallography; hallucinogens; serotonin receptor; structure-function