GPCR-G protein selectivity revealed by structural pharmacology

Abstract

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.

Keywords: G protein; GPCR; bias signaling; selectivity; structural pharmacology.

Figure 1.

Comparison of G_i1 and G_oA structures. (A-C) Comparison of G_i1 structures (KOR-G_i1: Orange; 5-HT_5A-G_i1: Blue; α_2BAR-G_i1: Cyan; CCR5-G_i1: Purple). (A) G_i1 subunit (orange) hydrogen bond interactions with KOR (grey). (B) Overlay of G_i1 subunit. (C) Movement of 5-HT_5A and α_2BAR α5 and TM6 respective to KOR. (D-G) Comparison of G_oA structures (KOR-G_oA: Green; 5-HT_5A-G_oA: Blue; α_2BAR-G_oA: Cyan; CCR6-G_oA: Purple). (D) G_oA subunit (green) hydrogen bond interactions with KOR (grey). (E) Overlay of G_oA subunit. (F) Movement of 5-HT_5A and α_2BAR α5 and TM6 respective to KOR. (G) Conserved hydrogen bond interactions with residues Y354^H5.26 and N347^H5.19 across structures. Structural figures were generated in PyMOL.

Figure 2.

Comparison of G_g and G_z structures. (A-F) Comparison of G_g structures (KOR-G_g: Pink; TAS2R46-G_g: Purple). (A) G_g subunit (pink) hydrogen bond interactions with KOR (grey). (B) Overlay of G_g subunit. (C) Similar G_g interactions found in both KOR and TAS2R46 structures. (D) Key interaction for KOR G_g recruitment which is not found with TAS2R46. (E) TAS2R46 has TM5 shifted closer to α5, allowing it to form more interactions. (F) ICL2 of TAS2R46 is shifted upward, preventing interaction with α5 and loops seen in KOR structure. (G) G_z subunit (teal) hydrogen bond interactions with KOR (grey). Structural figures were generated in PyMOL.