变构调节
大麻素受体
变构调节剂
G蛋白偶联受体
反激动剂
化学
兴奋剂
结合位点
大麻素
受体
生物化学
作者
Zhenhua Shao,Wei Yan,Karen Chapman,Karthik Ramesh,Aaron J. Ferrell,Jie Yin,Xuehui Wang,Qingping Xu,Daniel M. Rosenbaum
标识
DOI:10.1038/s41589-019-0387-2
摘要
The CB1 receptor mediates the central nervous system response to cannabinoids, and is a drug target for pain, anxiety and seizures. CB1 also responds to allosteric modulators, which influence cannabinoid binding and efficacy. To understand the mechanism of these compounds, we solved the crystal structure of CB1 with the negative allosteric modulator (NAM) ORG27569 and the agonist CP55940. The structure reveals that the NAM binds to an extrahelical site within the inner leaflet of the membrane, which overlaps with a conserved site of cholesterol interaction in many G protein-coupled receptors (GPCRs). The ternary structure with ORG27569 and CP55940 captures an intermediate state of the receptor, in which aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite the large contraction of the orthosteric pocket. The structure illustrates a potential strategy for drug modulation of CB1 and other class A GPCRs.
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