Structure of an allosteric modulator bound to the CB1 cannabinoid receptor

Zhenhua Shao, Wei Yan, Karen Chapman, Karthik Ramesh, Aaron J. Ferrell, Jie Yin, Xuehui Wang, Qingping Xu, Daniel M. Rosenbaum

Research output: Contribution to journalArticlepeer-review

77 Scopus citations


The CB1 receptor mediates the central nervous system response to cannabinoids, and is a drug target for pain, anxiety and seizures. CB1 also responds to allosteric modulators, which influence cannabinoid binding and efficacy. To understand the mechanism of these compounds, we solved the crystal structure of CB1 with the negative allosteric modulator (NAM) ORG27569 and the agonist CP55940. The structure reveals that the NAM binds to an extrahelical site within the inner leaflet of the membrane, which overlaps with a conserved site of cholesterol interaction in many G protein-coupled receptors (GPCRs). The ternary structure with ORG27569 and CP55940 captures an intermediate state of the receptor, in which aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite the large contraction of the orthosteric pocket. The structure illustrates a potential strategy for drug modulation of CB1 and other class A GPCRs.

Original languageEnglish (US)
Pages (from-to)1199-1205
Number of pages7
JournalNature chemical biology
Issue number12
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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