Crystal structure of an LSD-bound human serotonin receptor
Daniel Wacker, Sheng Wang, John D. Mccorvy, Robin M. Betz, A. Venkatakrishnan, A. Levit, K. Lansu, Z. L. Schools, Tao Che, D. Nichols, Brian K. Shoichet, Ron O. Dror, B. Roth
Cell January 26, 2017 DOI: 10.1016/j.cell.2016.12.033 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with structural biology and molecular dynamics simulations Peer reviewed |
|---|---|
| Topics | LSD Serotonin |
| Citations | 466 |
| Key findings | 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.