Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell 2017 Jan 26;168(3):377-389.e12
Date
01/28/2017Pubmed ID
28129538Pubmed Central ID
PMC5289311DOI
10.1016/j.cell.2016.12.033Scopus ID
2-s2.0-85010703450 (requires institutional sign-in at Scopus site) 390 CitationsAbstract
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.
Author List
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 BLAuthor
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ArrestinCrystallography, X-Ray
Humans
Kinetics
Lysergic Acid Diethylamide
Models, Chemical
Molecular Dynamics Simulation
Receptor, Serotonin, 5-HT2B
