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Structure paper

TitleMolecular mechanism of allosteric modulation for the cannabinoid receptor CB1.
Journal, issue, pagesNat Chem Biol, Vol. 18, Issue 8, Page 831-840, Year 2022
Publish dateMay 30, 2022
AuthorsXin Yang / Xuehui Wang / Zheng Xu / Chao Wu / Yangli Zhou / Yifei Wang / Guifeng Lin / Kan Li / Ming Wu / Anjie Xia / Jingming Liu / Lin Cheng / Jun Zou / Wei Yan / Zhenhua Shao / Shengyong Yang /
PubMed AbstractGiven 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 ...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.
External linksNat Chem Biol / PubMed:35637350
MethodsEM (single particle) / X-ray diffraction
Resolution2.7 - 3.36 Å
Structure data

32850

7wv9

EMDB-32850, PDB-7wv9:
Allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid receptor 1 in complex with Gi protein
Method: EM (single particle) / Resolution: 3.36 Å

PDB-7fee:
Crystal structure of the allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid receptor 1
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

ChemComp-9GF:
2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol

ChemComp-7IC:
6-methyl-3-[(1S)-2-nitro-1-thiophen-2-yl-ethyl]-2-phenyl-1H-indole

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER

ChemComp-GOL:
GLYCEROL

ChemComp-OLC:
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate

ChemComp-OLA:
OLEIC ACID

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • pyrococcus abyssi ge5 (archaea)
KeywordsMEMBRANE PROTEIN / signal protein / GPCR / Complex / agonist

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