Crystal Structure of an LSD-Bound Human Serotonin Receptor
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 selec...
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Published in | Cell Vol. 168; no. 3; pp. 377 - 389.e12 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
26.01.2017
Elsevier |
Subjects | |
Online Access | Get full text |
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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 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.
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•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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 ObjectType-Commentary-3 content type line 23 USDOE National Institutes of Health (NIH) Lead Contact Co-first author |
ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2016.12.033 |