9xn4 | pdb_00009xn4

Glucagon receptor-Gs complex activated by the small molecule agonist SIM1

spinqualitylabelsall models 9xn4, resolution 2.53Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9xn4 is a 5 chain structure with sequence from Bos taurus, Homo sapiens, Lama glama and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.53Å Ligands: A1E0Y Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GBB1_RAT Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. Publication Abstract from PubMed The glucagon receptor (GCGR) and gastric inhibitory polypeptide receptor (GIPR) are class B GPCRs that regulate glucose homeostasis and energy balance, making them key targets for type 2 diabetes and obesity. Achieving preferential G(s) signaling at these receptors with small molecules remains an unmet challenge. Here, we report SIM1, developed through optimization of the PCO371 scaffold, which exhibits preferential G(s) signaling at GCGR and GIPR with minimal detectable beta-arrestin recruitment and substantially improved efficacy at GIPR. Cryo-EM structures of SIM1-GCGR-G(s) (2.53 A) and SIM1-GIPR-G(s) (2.74 A) reveal a shared intracellular allosteric interface at the receptor-G protein coupling region, distinct from extracellular peptide recognition. Structural comparison with GLP1R suggests that intracellular conformational constraints contribute to differential SIM1 responsiveness, which is restored by targeted mutations. Guided by these insights, analogs SIM2 and SIM3 exhibited up to 20-fold enhanced potency while maintaining an apparent preferential G(s) signaling profile. These findings reveal a conserved intracellular allosteric activation mechanism across multiple class B GPCRs and identify SIM1 and its analogs as valuable chemical tools for investigating receptor-specific intracellular allosteric regulation and G protein-preferential signaling. Structural basis for small-molecule agonism at GCGR and GIPR via a conserved intracellular allosteric site.,He Q, Shan H, Hu W, Eric Xu H, Zhao LH Acta Pharmacol Sin. 2026 Sep 14. doi: 10.1038/s41401-026-01923-5. PMID:42736455 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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