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TitleStructure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 121, Issue 24, Page e2321532121, Year 2024
Publish dateJun 11, 2024
AuthorsSiyuan Shen / Chao Wu / Guifeng Lin / Xin Yang / Yangli Zhou / Chang Zhao / Zhuang Miao / Xiaowen Tian / Kexin Wang / Zhiqian Yang / Zhiyu Liu / Nihong Guo / Yueshan Li / Anjie Xia / Pei Zhou / Jingming Liu / Wei Yan / Bowen Ke / Shengyong Yang / Zhenhua Shao /
PubMed Abstract is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other ... is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and β-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.
External linksProc Natl Acad Sci U S A / PubMed:38830102 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 3.4 Å
Structure data

35511

8ikg

EMDB-35511, PDB-8ikg:
Cryo-EM structure of human receptor with G proteins
Method: EM (single particle) / Resolution: 3.4 Å

35512

8ikh

EMDB-35512, PDB-8ikh:
Cryo-EM structure of human receptor with G proteins
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals


ChemComp, No image

ChemComp-Q2B:
Unknown entry


ChemComp, No image

ChemComp-Q2L:
Unknown entry

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / complex / allosteric modulator

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