3L3N

Testis ACE co-crystal structure with novel inhibitor lisW

Summary for 3L3N

• Entry DOI: 10.2210/pdb3l3n/pdb
• Related: 1o86 1o8a 1uze 1uzf 2iul 3bkk
• Descriptor: Angiotensin-converting enzyme, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (6 entities in total)
• Functional Keywords: enzyme-inhibitor complex, angiotensin-converting enzyme (ace) inhibitors, testis, carboxypeptidase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 69482.67

Authors

Watermeyer, J.M.,Kroger, W.L.,O'Neil, H.G.,Sewell, B.T.,Sturrock, E.D. (deposition date: 2009-12-17, release date: 2010-04-28, Last modification date: 2024-10-30)

Primary citation

Watermeyer, J.M.,Kroger, W.L.,O'Neill, H.G.,Sewell, B.T.,Sturrock, E.D.
Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril.
Biochem.J., 428:67-74, 2010

PubMed Abstract: Human ACE (angiotensin-converting enzyme) (EC 3.4.15.1) is an important drug target because of its role in the regulation of blood pressure via the renin-angiotensin-aldosterone system. Somatic ACE comprises two homologous domains, the differing substrate preferences of which present a new avenue for domain-selective inhibitor design. We have co-crystallized lisW-S, a C-domain-selective derivative of the drug lisinopril, with human testis ACE and determined a structure using X-ray crystallography to a resolution of 2.30 A (1 A=0.1 nm). In this structure, lisW-S is seen to have a similar binding mode to its parent compound lisinopril, but the P2' tryptophan moiety takes a different conformation to that seen in other inhibitors having a tryptophan residue in this position. We have examined further the domain-specific interactions of this inhibitor by mutating C-domain-specific active-site residues to their N domain equivalents, then assessing the effect of the mutation on inhibition by lisW-S using a fluorescence-based assay. Kinetics analysis shows a 258-fold domain-selectivity that is largely due to the co-operative effect of C-domain-specific residues in the S2' subsite. The high affinity and selectivity of this inhibitor make it a good lead candidate for cardiovascular drug development.

PubMed: 20233165
DOI: 10.1042/BJ20100056

Experimental method

X-RAY DIFFRACTION (2.3 Å)