Structure of an Allosteric Modulator Bound to the CB1 Cannabinoid Receptor

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2019 Oct 30

PMID 31659318

Citations 80

Authors

Zhenhua Shao

Wei Yan

Karen Chapman

Karthik Ramesh

Aaron J Ferrell

Jie Yin

Xuehui Wang

Qingping Xu

Daniel M Rosenbaum

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Identification of a Cannabinoid Receptor 2 Allosteric Site Using Computational Modeling and Pharmacological Analysis.

Farooq Z, Delre P, Iliadis S, Mangiatordi G, Contino M, Howell L ACS Pharmacol Transl Sci. 2025; 8(2):423-434.

PMID: 39974643 PMC: 11833715. DOI: 10.1021/acsptsci.4c00547.

Advances in cannabinoid receptors pharmacology: from receptor structural insights to ligand discovery.

Shen S, Wu C, Yang Z, Wang K, Shao Z, Yan W Acta Pharmacol Sin. 2025; .

PMID: 39910211 DOI: 10.1038/s41401-024-01472-9.

Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein.

Han Y, Dawson J, DeMarco K, Rouen K, Ngo K, Bekker S iScience. 2025; 28(2):111741.

PMID: 39898043 PMC: 11787599. DOI: 10.1016/j.isci.2024.111741.

Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS.

Zhao J, Shen Q, Yong X, Li X, Tian X, Sun S Nat Struct Mol Biol. 2025; .

PMID: 39824976 DOI: 10.1038/s41594-024-01470-9.

Structural basis of THC analog activity at the Cannabinoid 1 receptor.

Thorsen T, Kulkarni Y, Sykes D, Boggild A, Drace T, Hompluem P Nat Commun. 2025; 16(1):486.

PMID: 39779700 PMC: 11711184. DOI: 10.1038/s41467-024-55808-4.

References

Mechoulam R, Parker L . The endocannabinoid system and the brain. Annu Rev Psychol. 2012; 64:21-47. DOI: 10.1146/annurev-psych-113011-143739. View

Whiting P, Wolff R, Deshpande S, Di Nisio M, Duffy S, Hernandez A . Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015; 313(24):2456-73. DOI: 10.1001/jama.2015.6358. View

Devinsky O, Cross J, Laux L, Marsh E, Miller I, Nabbout R . Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017; 376(21):2011-2020. DOI: 10.1056/NEJMoa1611618. View

Kunos G, Osei-Hyiaman D, Batkai S, Sharkey K, Makriyannis A . Should peripheral CB(1) cannabinoid receptors be selectively targeted for therapeutic gain?. Trends Pharmacol Sci. 2008; 30(1):1-7. PMC: 2748782. DOI: 10.1016/j.tips.2008.10.001. View

Thal D, Glukhova A, Sexton P, Christopoulos A . Structural insights into G-protein-coupled receptor allostery. Nature. 2018; 559(7712):45-53. DOI: 10.1038/s41586-018-0259-z. View

Price M, Baillie G, Thomas A, Stevenson L, Easson M, Goodwin R . Allosteric modulation of the cannabinoid CB1 receptor. Mol Pharmacol. 2005; 68(5):1484-95. DOI: 10.1124/mol.105.016162. View

Baillie G, Horswill J, Anavi-Goffer S, Reggio P, Bolognini D, Abood M . CB(1) receptor allosteric modulators display both agonist and signaling pathway specificity. Mol Pharmacol. 2012; 83(2):322-38. PMC: 3558808. DOI: 10.1124/mol.112.080879. View

Fay J, Farrens D . A key agonist-induced conformational change in the cannabinoid receptor CB1 is blocked by the allosteric ligand Org 27569. J Biol Chem. 2012; 287(40):33873-82. PMC: 3460482. DOI: 10.1074/jbc.M112.352328. View

Fay J, Farrens D . Structural dynamics and energetics underlying allosteric inactivation of the cannabinoid receptor CB1. Proc Natl Acad Sci U S A. 2015; 112(27):8469-74. PMC: 4500223. DOI: 10.1073/pnas.1500895112. View

10.

Khurana L, Mackie K, Piomelli D, Kendall D . Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities. Neuropharmacology. 2017; 124:3-12. PMC: 5540789. DOI: 10.1016/j.neuropharm.2017.05.018. View

11.

Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J . High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature. 2016; 540(7634):602-606. PMC: 5433929. DOI: 10.1038/nature20613. View

12.

Suno R, Lee S, Maeda S, Yasuda S, Yamashita K, Hirata K . Structural insights into the subtype-selective antagonist binding to the M muscarinic receptor. Nat Chem Biol. 2018; 14(12):1150-1158. PMC: 6462224. DOI: 10.1038/s41589-018-0152-y. View

13.

Hua T, Vemuri K, Nikas S, Laprairie R, Wu Y, Qu L . Crystal structures of agonist-bound human cannabinoid receptor CB. Nature. 2017; 547(7664):468-471. PMC: 5793864. DOI: 10.1038/nature23272. View

14.

Kumar K, Shalev-Benami M, Robertson M, Hu H, Banister S, Hollingsworth S . Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell. 2019; 176(3):448-458.e12. PMC: 6461403. DOI: 10.1016/j.cell.2018.11.040. View

15.

Johnson M, Melvin L, Althuis T, Bindra J, Harbert C, Milne G . Selective and potent analgetics derived from cannabinoids. J Clin Pharmacol. 1981; 21(S1):271S-282S. DOI: 10.1002/j.1552-4604.1981.tb02605.x. View

16.

Herkenham M, Lynn A, Little M, Johnson M, Melvin L, De Costa B . Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. 1990; 87(5):1932-6. PMC: 53598. DOI: 10.1073/pnas.87.5.1932. View

17.

Shim J, Bertalovitz A, Kendall D . Identification of essential cannabinoid-binding domains: structural insights into early dynamic events in receptor activation. J Biol Chem. 2011; 286(38):33422-35. PMC: 3190901. DOI: 10.1074/jbc.M111.261651. View

18.

Murphy J, Kendall D . Integrity of extracellular loop 1 of the human cannabinoid receptor 1 is critical for high-affinity binding of the ligand CP 55,940 but not SR 141716A. Biochem Pharmacol. 2003; 65(10):1623-31. DOI: 10.1016/s0006-2952(03)00155-2. View

19.

Ahn K, Bertalovitz A, Mierke D, Kendall D . Dual role of the second extracellular loop of the cannabinoid receptor 1: ligand binding and receptor localization. Mol Pharmacol. 2009; 76(4):833-42. PMC: 2769047. DOI: 10.1124/mol.109.057356. View

20.

Singh R, Hurst D, Lynch D, Reggio P, Guarnieri F . Activation of the cannabinoid CB1 receptor may involve a W6 48/F3 36 rotamer toggle switch. J Pept Res. 2002; 60(6):357-70. DOI: 10.1034/j.1399-3011.2002.21065.x. View