High-resolution crystal structure of the human CB1 cannabinoid receptor

Zhenhua Shao, Jie Yin, Karen Chapman, Magdalena Grzemska, Lindsay Clark, Junmei Wang, Daniel M. Rosenbaum

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

The human cannabinoid G-protein-coupled receptors (GPCRs) CB1 and CB2 mediate the functional responses to the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) and to the widely consumed plant phytocannabinoid Δ9-tetrahydrocannabinol (THC). The cannabinoid receptors have been the targets of intensive drug discovery efforts, because modulation of these receptors has therapeutic potential to control pain, epilepsy, obesity, and other disorders. Although much progress in understanding the biophysical properties of GPCRs has recently been made, investigations of the molecular mechanisms of the cannabinoids and their receptors have lacked high-resolution structural data. Here we report the use of GPCR engineering and lipidic cubic phase crystallization to determine the structure of the human CB1 receptor bound to the inhibitor taranabant at 2.6-Å resolution. We found that the extracellular surface of CB1, including the highly conserved membrane-proximal N-terminal region, is distinct from those of other lipid-activated GPCRs, forming a critical part of the ligand-binding pocket. Docking studies further demonstrate how this same pocket may accommodate the cannabinoid agonist THC. Our CB1 structure provides an atomic framework for studying cannabinoid receptor function and will aid the design and optimization of therapeutic modulators of the endocannabinoid system.

Original languageEnglish (US)
Pages (from-to)602-606
Number of pages5
JournalNature
Volume540
Issue number7634
DOIs
StatePublished - Dec 22 2016

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Cannabinoid Receptor CB1
G-Protein-Coupled Receptors
Cannabinoid Receptors
Endocannabinoids
Dronabinol
Cannabinoid Receptor Agonists
Cannabinoids
Drug Discovery
Crystallization
Epilepsy
Obesity
Ligands
Lipids
Pain
Membranes
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

High-resolution crystal structure of the human CB1 cannabinoid receptor. / Shao, Zhenhua; Yin, Jie; Chapman, Karen; Grzemska, Magdalena; Clark, Lindsay; Wang, Junmei; Rosenbaum, Daniel M.

In: Nature, Vol. 540, No. 7634, 22.12.2016, p. 602-606.

Research output: Contribution to journalArticle

Shao, Z, Yin, J, Chapman, K, Grzemska, M, Clark, L, Wang, J & Rosenbaum, DM 2016, 'High-resolution crystal structure of the human CB1 cannabinoid receptor', Nature, vol. 540, no. 7634, pp. 602-606. https://doi.org/10.1038/nature20613
Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J et al. High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature. 2016 Dec 22;540(7634):602-606. https://doi.org/10.1038/nature20613
Shao, Zhenhua ; Yin, Jie ; Chapman, Karen ; Grzemska, Magdalena ; Clark, Lindsay ; Wang, Junmei ; Rosenbaum, Daniel M. / High-resolution crystal structure of the human CB1 cannabinoid receptor. In: Nature. 2016 ; Vol. 540, No. 7634. pp. 602-606.
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