Abstract
Hypertension is regulated through both the central and systemic renin-angiotensin systems. 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.
Highlights
Human aminopeptidase A (APA) regulates central hypertension through its calcium-modulated preference to cleave N-terminal acidic residues from peptides
This study reveals the structural basis for the different APA-inhibiting potencies of peptidomimetic inhibitors. These results provide an understanding of the substrate specificity and calcium modulation of APA in central hypertension regulation and will guide the development of a new class of brain-targeting APA inhibitors to treat hypertension
Angiotensin III is produced by the action of APA on angiotensin II and is converted to angiotensin IV by aminopeptidase N (APN) (Fig. 1) [11, 12]
Summary
Human aminopeptidase A (APA) regulates central hypertension through its calcium-modulated preference to cleave N-terminal acidic residues from peptides. 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. Of the peptidomimetic inhibitors of APA, amastatin has higher potency than bestatin by fitting better in the S1 pocket and interacting 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. The atomic coordinates and structure factors (codes 4KX7, 4KX8, 4KX9, 4KXA, 4KXB, 4KXC, and 4KXD) have been deposited in the Protein Data Bank (http://wwpdb.org/)
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