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 Å (1 Å=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.
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Research Article|
April 28 2010
Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril
Jean M. Watermeyer;
Jean M. Watermeyer
1Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, 7935, South Africa
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Wendy L. Kröger;
Wendy L. Kröger
1Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, 7935, South Africa
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Hester G. O'Neill;
Hester G. O'Neill
1
1Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, 7935, South Africa
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B. Trevor Sewell;
B. Trevor Sewell
1Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, 7935, South Africa
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Edward D. Sturrock
Edward D. Sturrock
2
1Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, 7935, South Africa
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
January 11 2010
Revision Received:
March 10 2010
Accepted:
March 17 2010
Accepted Manuscript online:
March 17 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 428 (1): 67–74.
Article history
Received:
January 11 2010
Revision Received:
March 10 2010
Accepted:
March 17 2010
Accepted Manuscript online:
March 17 2010
Citation
Jean M. Watermeyer, Wendy L. Kröger, Hester G. O'Neill, B. Trevor Sewell, Edward D. Sturrock; Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril. Biochem J 15 May 2010; 428 (1): 67–74. doi: https://doi.org/10.1042/BJ20100056
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