GPCR-G protein selectivity revealed by structural pharmacology.

Sarah M Bernhard, Jianming Han, Tao Che

The FEBS journal 2024 Jul

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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. © 2023 Federation of European Biochemical Societies.

Citation

Sarah M Bernhard, Jianming Han, Tao Che. GPCR-G protein selectivity revealed by structural pharmacology. The FEBS journal. 2024 Jul;291(13):2784-2791