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Structural Insights into Central Hypertension Regulation by Human Aminopeptidase A

Published: Wednesday, July 31, 2013
Last Updated: Wednesday, July 31, 2013
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This study determined the crystal structures of APA complexed with different ligands and calcium.

Abstract
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.


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