3BKL

Testis ACE co-crystal structure with ketone ACE inhibitor kAW

3BKL の概要

• エントリーDOI: 10.2210/pdb3bkl/pdb
• 関連するPDBエントリー: 1O86 1O8A 1UZE 1UZF 2IUL 2IUX 3BKK
• 分子名称: Angiotensin-converting enzyme, somatic isoform, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: enzyme-inhibitor complex, gem-diol, domain-selective, carboxypeptidase, glycoprotein, hydrolase, membrane, metal-binding, metalloprotease, phosphoprotein, protease, secreted, transmembrane
• 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: 70229.32

構造登録者

Watermeyer, J.M.,Kroger, W.L.,O'Neill, H.G.,Sewell, B.T.,Sturrock, E.D. (登録日: 2007-12-07, 公開日: 2008-06-10, 最終更新日: 2024-11-13)

主引用文献

Watermeyer, J.M.,Kroger, W.L.,O'Neill, H.G.,Sewell, B.T.,Sturrock, E.D.
Probing the basis of domain-dependent inhibition using novel ketone inhibitors of Angiotensin-converting enzyme
Biochemistry, 47:5942-5950, 2008

PubMed Abstract: Human angiotensin-converting enzyme (ACE) has two homologous domains, the N and C domains, with differing substrate preferences. X-ray crystal structures of the C and N domains complexed with various inhibitors have allowed identification of active site residues that might be important for the molecular basis of this selectivity. However, it is unclear to what extent the different residues contribute to substrate domain selectivity. Here, cocrystal structures of human testis ACE, equivalent to the C domain, have been determined with two novel C domain-selective ketomethylene inhibitors, (5 S)-5-[( N-benzoyl)amino]-4-oxo-6-phenylhexanoyl- l-tryptophan (kAW) and (5 S)-5-[( N-benzoyl)amino]-4-oxo-6-phenylhexanoyl- l-phenylalanine (kAF). The ketone groups of both inhibitors bind to the zinc ion as a hydrated geminal diolate, demonstrating the ability of the active site to catalyze the formation of the transition state. Moreover, active site residues involved in inhibitor binding have been mutated to their N domain counterparts, and the effect of the mutations on inhibitor binding has been determined. The C domain selectivity of these inhibitors was found to result from interactions between bulky hydrophobic side chain moieties and C domain-specific residues F391, V518, E376, and V380 (numbering of testis ACE). Mutation of these residues decreased the affinity for the inhibitors 4-20-fold. T282, V379, E403, D453, and S516 did not contribute individually to C domain-selective inhibitor binding. Further domain-selective inhibitor design should focus on increasing both the affinity and selectivity of the side chain moieties.

PubMed: 18457420
DOI: 10.1021/bi8002605

実験手法

X-RAY DIFFRACTION (2.18 Å)