The ICL2 hub and intracellular allosterism
Advances in structural biology have revealed intracellular allosteric pockets that fine-tune transducer coupling and orthosteric ligand responses.
Intracellular biased allosteric modulators can stabilize receptor conformations that favor specific transducer coupling or engagement, enabling pathway
selective responses beyond orthosteric ligands.
The intracellular loop 2 site can act as a tunable hub for biased G protein-coupled receptor modulation, offering a strategic target for pathway-selective allosteric modulator design.
Structure-guided and affinity-based discovery, AI-assisted design, and medicinal chemistry can accelerate intracellular allosteric modulator discovery and optimization.
https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(26)00227-0
