Molecular mechanisms for subtype selectivity of kinin receptors' antagonists.

The kinin receptors B1R and B2R act as key regulators within the kallikrein-kinin system, mediating vasodilation, inflammation, and pain. Antagonists targeting these receptors have shown therapeutic potential in the treatment of angioedema, pancreatitis, and asthma. However, the molecular mechanisms underlying subtype selectivity of kinin receptors' antagonists remain unclear. Here we report three cryo-electron microscopy (cryo-EM) structures of B1R in complex with the peptide antagonist R715 and small-molecule antagonist ELN441958, as well as B2R in complex with small-molecule antagonist Win64338. Together with functional assays and molecular docking, these structures unveil the molecular basis of antagonist binding modes in kinin receptors. Three non-conserved residues at the bottom of the ligand binding pocket are identified to confer the antagonist selectivity to B1R and B2R. Furthermore, our results reveal a shared mechanism for antagonism in both B1R and B2R, wherein the antagonist binding restricts the conformational changes of the toggle switch tryptophan residue. Collectively, these insights lay the foundation for the structure-based design of selective antagonists targeting B1R and B2R.