4KXA

Crystal structure of human aminopeptidase A complexed with aspartate and calcium

4KXA の概要

• エントリーDOI: 10.2210/pdb4kxa/pdb
• 関連するPDBエントリー: 4KX7 4KX8 4KX9 4KXB 4KXC 4KXD
• 関連するBIRD辞書のPRD_ID: PRD_900017
• 分子名称: Glutamyl aminopeptidase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• 機能のキーワード: zinc-aminopeptidase, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 106353.27

構造登録者

Yang, Y.,Liu, C.,Lin, Y.Y.,Li, F. (登録日: 2013-05-24, 公開日: 2013-07-31, 最終更新日: 2024-10-16)

主引用文献

Yang, Y.,Liu, C.,Lin, Y.L.,Li, F.
Structural insights into central hypertension regulation by human aminopeptidase a.
J.Biol.Chem., 288:25638-25645, 2013

PubMed 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.

PubMed: 23888046
DOI: 10.1074/jbc.M113.494955

実験手法

X-RAY DIFFRACTION (2.4 Å)