6kqi

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Structure of an allosteric modulator bound to the CB1 cannabinoid receptor

Structural highlights

6kqi is a 1 chain structure with sequence from Homo sapiens and Pyrococcus abyssi GE5. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.245Å
Ligands:9GF, 9GL, OLA, OLC, PEG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q9V2J8_PYRAB CNR1_HUMAN Involved in cannabinoid-induced CNS effects. Acts by inhibiting adenylate cyclase. Could be a receptor for anandamide. Inhibits L-type Ca(2+) channel current. Isoform 2 and isoform 3 have altered ligand binding.[1]

Publication Abstract from PubMed

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.

Structure of an allosteric modulator bound to the CB1 cannabinoid receptor.,Shao Z, Yan W, Chapman K, Ramesh K, Ferrell AJ, Yin J, Wang X, Xu Q, Rosenbaum DM Nat Chem Biol. 2019 Oct 28. pii: 10.1038/s41589-019-0387-2. doi:, 10.1038/s41589-019-0387-2. PMID:31659318[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
19 reviews cite this structure
Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products.
An et al. (2020)
18 more
31 other articles
No citations found

References

  1. ↑ Ryberg E, Vu HK, Larsson N, Groblewski T, Hjorth S, Elebring T, Sjogren S, Greasley PJ. Identification and characterisation of a novel splice variant of the human CB1 receptor. FEBS Lett. 2005 Jan 3;579(1):259-64. PMID:15620723 doi:http://dx.doi.org/10.1016/j.febslet.2004.11.085
  2. ↑ Shao Z, Yan W, Chapman K, Ramesh K, Ferrell AJ, Yin J, Wang X, Xu Q, Rosenbaum DM. Structure of an allosteric modulator bound to the CB1 cannabinoid receptor. Nat Chem Biol. 2019 Oct 28. pii: 10.1038/s41589-019-0387-2. doi:, 10.1038/s41589-019-0387-2. PMID:31659318 doi:http://dx.doi.org/10.1038/s41589-019-0387-2

Contents


PDB ID 6kqi

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OCA

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