3BKK

Tesis ACE co-crystal structure with ketone ACE inhibitor kAF

Summary for 3BKK

• Entry DOI: 10.2210/pdb3bkk/pdb
• Related: 1O86 1O8A 1UZE 1UZF 2IUL 2IUX 3BKL
• Descriptor: 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, ... (7 entities in total)
• Functional Keywords: enzyme-inhibitor complex, gem-diol, domain-selective, carboxypeptidase, glycoprotein, hydrolase, membrane, metal-binding, metalloprotease, phosphoprotein, protease, secreted, transmembrane
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 69921.05

Authors

Watermeyer, J.M.,Kroger, W.L.,O'Neill, H.G.,Sewell, B.T.,Sturrock, E.D. (deposition date: 2007-12-07, release date: 2008-06-10, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.17 Å)