9XN3

Glucose-dependent insulinotropic polypeptide receptor-Gs complex activated by the small molecule agonist SIM1

This is a non-PDB format compatible entry.

Summary for 9XN3

• Entry DOI: 10.2210/pdb9xn3/pdb
• EMDB information: 67037
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: small molecule agonist, complex, gipr, membrane protein, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Bos taurus (human); More
• Total number of polymer chains: 5
• Total formula weight: 148655.17

Authors

Xu, H.E.,Shan, H.,He, Q.,Zhao, L. (deposition date: 2025-11-12, release date: 2026-09-30)

Primary citation

He, Q.,Shan, H.,Hu, W.,Eric Xu, H.,Zhao, L.H.
Structural basis for small-molecule agonism at GCGR and GIPR via a conserved intracellular allosteric site.
Acta Pharmacol.Sin., 2026

PubMed Abstract: 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 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 signaling at GCGR and GIPR with minimal detectable β-arrestin recruitment and substantially improved efficacy at GIPR. Cryo-EM structures of SIM1-GCGR-G (2.53 Å) and SIM1-GIPR-G (2.74 Å) 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 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.

PubMed: 42736455
DOI: 10.1038/s41401-026-01923-5

Experimental method

ELECTRON MICROSCOPY (2.74 Å)