Title : Structural insights into central hypertension regulation by human
aminopeptidase A . Hypertension is regulated through both the central and systemic
renin-angiotensin systems
Abstract :
- In the central renin-angiotensin system, 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, whereas 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 the design and development of brain-targeting antihypertensive APA inhibitors