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D Wacker, S Wang, JD McCorvy, RM Betz, AJ Venkatakrishnan, A Levit, K Lansu, ZL Schools, T Che, DE Nichols, BK Shoichet, RO Dror and BL Roth
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.
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Concepts
5-HT1A receptor, Signal transduction, Receptor, Agonist, 5-HT receptor, 5-HT2B receptor, 5-HT2C receptor, Serotonin
MeSH headings
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