7WV9

Allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid receptor 1 in complex with Gi protein

Summary for 7WV9

• Entry DOI: 10.2210/pdb7wv9/pdb
• EMDB information: 32850
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-2, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: complex, agonist, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 170389.00

Authors

Xu, Z.,Shao, Z. (deposition date: 2022-02-10, release date: 2022-06-15, Last modification date: 2024-11-13)

Primary citation

Yang, X.,Wang, X.,Xu, Z.,Wu, C.,Zhou, Y.,Wang, Y.,Lin, G.,Li, K.,Wu, M.,Xia, A.,Liu, J.,Cheng, L.,Zou, J.,Yan, W.,Shao, Z.,Yang, S.
Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1.
Nat.Chem.Biol., 18:831-840, 2022

PubMed Abstract: Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we report the crystallographic and cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator (PAM) ZCZ011. These structures show that ZCZ011 binds to an extrahelical site in the transmembrane 2 (TM2)-TM3-TM4 surface. Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement is critical for the propagation of allosteric signals. ZCZ011 exerts a PAM effect by promoting TM2 rearrangement in favor of receptor activation and increasing the population of receptors that adopt an active conformation. In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface and exerts a NAM effect by impeding the TM2 rearrangement. Our findings fill a gap in the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators.

PubMed: 35637350
DOI: 10.1038/s41589-022-01038-y

Experimental method

ELECTRON MICROSCOPY (3.36 Å)