5TVN

Crystal structure of the LSD-bound 5-HT2B receptor

Summary for 5TVN

• Entry DOI: 10.2210/pdb5tvn/pdb
• Descriptor: Chimera protein of human 5-hydroxytryptamine receptor 2B and E. Coli soluble cytochrome b562, (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide, CHOLESTEROL, ... (7 entities in total)
• Functional Keywords: lsd, gpcr, serotonin receptor, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 46500.73

Authors

Wacker, D.,Wang, S.,McCorvy, J.D.,Betz, R.M.,Venkatakrishnan, A.J.,Levit, A.,Lansu, K.,Schools, Z.L.,Che, T.,Nichols, D.E.,Shoichet, B.K.,Dror, R.O.,Roth, B.L. (deposition date: 2016-11-09, release date: 2017-02-01, Last modification date: 2024-11-13)

Primary citation

Wacker, D.,Wang, S.,McCorvy, J.D.,Betz, R.M.,Venkatakrishnan, A.J.,Levit, A.,Lansu, K.,Schools, Z.L.,Che, T.,Nichols, D.E.,Shoichet, B.K.,Dror, R.O.,Roth, B.L.
Crystal Structure of an LSD-Bound Human Serotonin Receptor.
Cell, 168:377-389.e12, 2017

PubMed Abstract: 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-HT. 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-HTR and 5-HTR-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. PAPERCLIP.

PubMed: 28129538
DOI: 10.1016/j.cell.2016.12.033

Experimental method

X-RAY DIFFRACTION (2.9 Å)