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-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-arresti

SUBMITTER: Wacker D 

PROVIDER: S-EPMC5289311 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature