GPCR-G protein selectivity revealed by structural pharmacology.
GPCR-G protein selectivity revealed by structural pharmacology.
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结构药理学揭示 GPCR-G 蛋白选择性。
DOI：
10.1111/febs.17049
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Che,Tao
中科院分区：
文献类型：
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作者：
Bernhard,SarahM;Han,Jianming;Che,Tao
受体-G 蛋白混杂在 A 类 G 蛋白偶联受体 (GPCR) 中经常观察到。特别是，GPCR 可以与来自不同家族（Gαs、Gαq/11、Gαi/o 和 Gα12/13）或相同家族亚型的 G 蛋白偶联。选择性/混杂性背后的分子基础尚未完全揭示。我们最近报道了通过冷冻电子显微镜 (cryo-EM) 测定的 kappa 阿片受体 (KOR) 与 Gi/o 家族亚型 [Gαi1、GαoA、Gαz 和 Gustducin (Gαg)] 复合物的结构。结构分析与药理学研究相结合，提供了对 Gi/o 亚型选择性的见解。鉴于不同 G 蛋白家族之间保守的序列同一性和激活机制，Gi/o 亚型内的发现可能会扩展到其他家族。了解 KOR-Gi/o 或 GPCR-G 蛋白选择性将有助于开发针对特定 G 蛋白亚型的更精确的治疗方法。
Receptor‐G protein promiscuity is frequently observed in class A G protein‐coupled receptors (GPCRs). In particular, GPCRs can couple with G proteins from different families (Gαs, Gαq/11, Gαi/o, and Gα12/13) or the same family subtypes. The molecular basis underlying the selectivity/promiscuity is not fully revealed. We recently reported the structures of kappa opioid receptor (KOR) in complex with the Gi/o family subtypes [Gαi1, GαoA, Gαz, and Gustducin (Gαg)] determined by cryo‐electron microscopy (cryo‐EM). The structural analysis, in combination with pharmacological studies, provides insights into Gi/o subtype selectivity. Given the conserved sequence identity and activation mechanism between different G protein families, the findings within Gi/o subtypes could be likely extended to other families. Understanding the KOR‐Gi/o or GPCR‐G protein selectivity will facilitate the development of more precise therapeutics targeting a specific G protein subtype.