Crystal Structure of an LSD-Bound Human Serotonin Receptor
Betz, R. M., Che, T., Dror, R. O., Lansu, K., Levit, A., McCorvy, J. D., Nichols, D. E., Roth, B. L., Schools, Z. L., Shoichet, B. K., Venkatakrishnan, A. J., Wacker, D., Wang, S.
This crystallography study analyzed the structure of LSD bound to a serotonin receptor and found that a branch of the receptor folds over the molecule while it is lodged into the binding pocket, and this lid-like structure secures LSD in place. This contributes to a slow dissociation rate of LSD, which forms the basis for its long-lasting effect. The authors suggest ways of introducing molecular mutations to selectively alter receptor signaling by increasing the mobility of this lid structure.
Abstract
Introduction: The prototypical hallucinogen LSD acts via serotonin receptors, and ...Methods: … here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B.Results: 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.Discussion: 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.