Crystal structure of an LSD-bound human serotonin receptor
Daniel Wacker, Sheng Wang, J. Mccorvy, Robin M. Betz, A. Venkatakrishnan, A. Levit, K. Lansu, Z. L. Schools, T. Che, D. Nichols, B. Shoichet, R. Dror, B. Roth
Cell January 26, 2017 Peer reviewed DOI: 10.1016/j.cell.2016.12.033 via Semantic Scholar 466 citations
Summary
The hallucinogen LSD binds to the human serotonin receptor 5-HT2B, and its crystal structure reveals conformational rearrangements that accommodate LSD, explaining the selectivity of its diethylamide group. LSD dissociates very slowly from both 5-HT2BR and 5-HT2AR, a key receptor for its psychoactive effects. Molecular dynamics simulations suggest that a 'lid' formed by extracellular loop 2 (EL2) at the binding pocket entrance may cause LSD's slow binding kinetics. A mutation that increases this lid's mobility greatly speeds up LSD's binding and selectively reduces LSD-mediated β-arrestin2 recruitment, providing a molecular explanation for LSD's actions at human serotonin receptors.
Study at a glance
| Design | experimental study with structural biology and molecular dynamics simulations |
|---|---|
| Key finding | LSD's slow binding kinetics at serotonin receptors may be due to a 'lid' formed by extracellular loop 2, and a mutation that increases lid mobility accelerates binding and selectively dampens β-arrestin2 recruitment. |
Abstract
SUMMARY 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 slowly 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.