6KPC

Crystal structure of an agonist bound GPCR

Summary for 6KPC

• Entry DOI: 10.2210/pdb6kpc/pdb
• Descriptor: Cannabinoid receptor 2,Endolysin, 7-[(6aR,9R,10aR)-1-Hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]- 7-methyloctanenitrile (2 entities in total)
• Functional Keywords: gpcr, lcp, agonist, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 56609.50

Authors

Li, X.T.,Hua, T.,Wu, L.J.,Makriyannis, A.,Wu, M.,Liu, Z.J. (deposition date: 2019-08-15, release date: 2020-02-12, Last modification date: 2024-10-30)

Primary citation

Hua, T.,Li, X.,Wu, L.,Iliopoulos-Tsoutsouvas, C.,Wang, Y.,Wu, M.,Shen, L.,Johnston, C.A.,Nikas, S.P.,Song, F.,Song, X.,Yuan, S.,Sun, Q.,Wu, Y.,Jiang, S.,Grim, T.W.,Benchama, O.,Stahl, E.L.,Zvonok, N.,Zhao, S.,Bohn, L.M.,Makriyannis, A.,Liu, Z.J.
Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-GiComplex Structures.
Cell, 180:655-, 2020

PubMed Abstract: Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with G, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.

PubMed: 32004463
DOI: 10.1016/j.cell.2020.01.008

Experimental method

X-RAY DIFFRACTION (3.2 Å)