Crystal Structure of an LSD-Bound Human Serotonin Receptor

Daniel Wacker, Sheng Wang, John D. McCorvy, Robin M. Betz, A. J. Venkatakrishnan, Anat Levit, Katherine Lansu, Zachary L. Schools, Tao Che, David E. Nichols, Brian K. Shoichet, Ron O. Dror, Bryan L. Roth

Research output: Research - peer-reviewArticle

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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-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. PaperClip

LanguageEnglish (US)
Pages377-389.e12
JournalCell
Volume168
Issue number3
DOIs
StatePublished - Jan 26 2017

Fingerprint

Lysergic Acid Diethylamide
Serotonin Receptors
Crystal structure
Serotonin
Kinetics
Hallucinogens
Stereochemistry
Molecular dynamics
Computer simulation
Molecular Dynamics Simulation
Mutation

Keywords

  • crystallography
  • GPCR
  • hallucinogens
  • serotonin receptor
  • structure-function

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wacker, D., Wang, S., McCorvy, J. D., Betz, R. M., Venkatakrishnan, A. J., Levit, A., ... Roth, B. L. (2017). Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell, 168(3), 377-389.e12. DOI: 10.1016/j.cell.2016.12.033

Crystal Structure of an LSD-Bound Human Serotonin Receptor. / 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.

In: Cell, Vol. 168, No. 3, 26.01.2017, p. 377-389.e12.

Research output: Research - peer-reviewArticle

Wacker, D, Wang, S, McCorvy, JD, Betz, RM, Venkatakrishnan, AJ, Levit, A, Lansu, K, Schools, ZL, Che, T, Nichols, DE, Shoichet, BK, Dror, RO & Roth, BL 2017, 'Crystal Structure of an LSD-Bound Human Serotonin Receptor' Cell, vol 168, no. 3, pp. 377-389.e12. DOI: 10.1016/j.cell.2016.12.033
Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A et al. Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell. 2017 Jan 26;168(3):377-389.e12. Available from, DOI: 10.1016/j.cell.2016.12.033
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./ Crystal Structure of an LSD-Bound Human Serotonin Receptor. In: Cell. 2017 ; Vol. 168, No. 3. pp. 377-389.e12
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