Crystal structure of an LSD-bound human serotonin receptor

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.

In the evidence

This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.

• State of the evidence: LSD ↑Supports

  The crystal structure of LSD bound to human 5-HT2B revealed slow dissociation kinetics, and simulations suggested an extracellular loop 2 'lid' explains this slow binding, with a mutation accelerating kinetics and dampening β-arrestin2 recruitment.

  Synthesized October 19, 2026

• State of the evidence: Serotonin ↑Supports

  The LSD-bound 5-HT2B crystal structure and simulations suggest a lid formed by extracellular loop 2 explains LSD's slow binding kinetics at serotonin receptors.

  Synthesized October 19, 2026

Comparable studies

Other experimental studies on LSD, most cited first.