TL;DR
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.
G protein-coupled receptors (GPCRs) often engage multiple intracellular transducers, yet the structural basis by which endogenous ligands influence G protein selectivity remains poorly understood. GPR119 is a lipid-activated receptor expressed in pancreatic β-cells and enteroendocrine L-cells, where it regulates glucos...
Cryo-electron microscopy structures of GPR84 in both active and inactive states revealed how different ligands interact with GPR84, influencing its signaling pathways, and provided a structural basis for designing selective modulators of GPR84, which could lead to new therapeutic strategies for diseases involving immun...
The glucagon-like peptide-1 receptor (GLP-1R) is a critical therapeutic target for metabolic diseases. GLP-1 receptor agonists (GLP-1RAs) have been developed to treat type 2 diabetes and promote weight loss. In this study, Gaussian accelerated molecular dynamics (GaMD) simulations, MM-PBSA calculations, and conformatio...
Targeting the orthosteric site of G protein-coupled receptors (GPCRs) has long dominated drug discovery, but intracellular allosteric modulators (AMs) provide new avenues to enhance selectivity and fine-tune signaling. Recent structural advances have illuminated intracellular allosteric pockets that act as conformation...
It is suggested that Gα protein selectivity is an allosterically encoded property of GPCRs and provide a conceptual framework for designing ligands and receptors with tailored Gα protein-biased signaling.
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