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-Structure paper
Title | Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1. |
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Journal, issue, pages | Nat Chem Biol, Vol. 18, Issue 8, Page 831-840, Year 2022 |
Publish date | May 30, 2022 |
![]() | Xin 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 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 ...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. |
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Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.7 - 3.36 Å |
Structure data | EMDB-32850, PDB-7wv9: ![]() PDB-7fee: |
Chemicals | ![]() ChemComp-CLR: ![]() ChemComp-9GF: ![]() ChemComp-7IC: ![]() ChemComp-PEG: ![]() ChemComp-GOL: ![]() ChemComp-OLC: ![]() ChemComp-OLA: ![]() ChemComp-HOH: |
Source |
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![]() | MEMBRANE PROTEIN / signal protein / GPCR / Complex / agonist |