Background: Angiotensin receptor (AT 1 R) blockers are critical therapeutics used to treat cardiovascular disease. Results: We solved the AT 1 R-olmesartan structure and identified specific interactions for olmesartan derivatives with different functions. Conclusion: Our results identified residues critical for the binding of different ligands and allosteric modulation by sodium ion. Significance: Our results provide new insights into the structural basis for ligand recognition and functional selectivity at AT 1 R.
Sodium ions are endogenous allosteric modulators of many G-protein-coupled receptors (GPCRs). Mutation of key residues in the sodium binding motif causes a striking effect on G-protein signaling. We report the crystal structures of agonist complexes for two variants in the first sodium coordination shell of the human A adenosine receptor, D52N and S91A. Both structures present an overall active-like conformation; however, the variants show key changes in the activation motif NPxxY. Changes in the hydrogen bonding network in this microswitch suggest a possible mechanism for modified G-protein signaling and enhanced thermal stability. These structures, signaling data, and thermal stability analysis with a panel of pharmacological ligands provide a basis for understanding the role of the sodium-coordinating residues on stability and G-protein signaling. Utilizing the DN variant is a promising method for stabilizing class A GPCRs to accelerate structural efforts and drug discovery.
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