Structural Insights into Central Hypertension Regulation by Human Aminopeptidase A
News Jul 31, 2013
Hypertension is regulated through both central and systemic renin-angiotensin systems (RASs). In central RAS, zinc-dependent aminopeptidase A (APA) up-regulates blood pressure by specifically cleaving the N-terminal aspartate, but not the adjacent arginine, from angiotensin II, a process facilitated by calcium. Here we determined the crystal structures of human APA and its complexes with different ligands, and identified a calcium-binding site in the S1 pocket of APA. Without calcium, the S1 pocket can bind both acidic and basic residues through formation of salt bridges with the charged side chains. In the presence of calcium, the binding of acidic residues is enhanced as they ligate the cation, while the binding of basic residues is no longer favorable due to charge repulsion. Of the peptidomimetic inhibitors of APA, amastatin has higher potency than bestatin by fitting better in the S1 pocket and interacting additionally with the S3’ subsite. These results explain the calcium-modulated substrate specificity of APA in central hypertension regulation and can guide design and development of brain-targeting antihypertensive APA inhibitors.
This study was published online in the Journal of Biological Chemistry and is free to access.