Crystal Structure of an LSD-Bound Human Serotonin Receptor

• Published in: Cell Vol. 168; no. 3; pp. 377 - 389.e12
• Main Authors: Wacker, Daniel, Wang, Sheng, McCorvy, John D., Betz, Robin M., Venkatakrishnan, A.J., Levit, Anat, Lansu, Katherine, Schools, Zachary L., Che, Tao, Nichols, David E., Shoichet, Brian K., Dror, Ron O., Roth, Bryan L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.01.2017; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Arrestin - chemistry; crystallography; Crystallography, X-Ray; GPCR; hallucinogens; Humans; Kinetics; Lysergic Acid Diethylamide - chemistry; Models, Chemical; Molecular Dynamics Simulation; Receptor, Serotonin, 5-HT2B - chemistry; serotonin receptor; structure-function; structure-function; serotonin receptor; GPCR; crystallography; hallucinogens
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.12.033

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 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. 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. [Display omitted] [Display omitted] •Crystal structure of the human 5-HT2B receptor bound to LSD is determined•LSD shows unexpected binding configuration in the orthosteric site•LSD has extremely slow on and off rate at 5-HT2B and 5-HT2A receptors•Accelerated LSD kinetics selectively reduce arrestin signaling at 5-HT2B and 5-HT2A The structure of LSD with a serotonin receptor reveals the basis for its long-lasting effects and suggests ways to selectively alter receptor signaling.