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Structure of angiotensin I-converting enzyme
E D Sturrock1, R Natesh, J M van Rooyen
1Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, 7925, Observatory, Cape Town, South Africa.
Cellular and Molecular Life Sciences : CMLS
|November 19, 2004
Summary
The three-dimensional structure of angiotensin-converting enzyme (ACE) reveals its active site and paves the way for designing new, selective ACE inhibitors.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Angiotensin-converting enzyme (ACE) is a crucial metallopeptidase in peptide metabolism.
- Previous ACE inhibitor design relied on homologous enzyme structures.
- Recent structural data for testis ACE (tACE) and AnCE offer new insights.
Purpose of the Study:
- To elucidate the three-dimensional structure of testis ACE (tACE).
- To compare tACE structure with homologous enzymes and inhibitor-bound forms.
- To provide a basis for rational design of novel ACE inhibitors.
Main Methods:
- X-ray crystallography of native tACE and lisinopril-tACE complex.
- Comparative structural analysis with carboxypeptidase A and thermolysin.
- Analysis of active site interactions and inhibitor binding.
Main Results:
- tACE possesses an ellipsoid structure with a constricted core channel housing the zinc-binding active site.
- Limited structural homology of tACE with carboxypeptidase A, moderate similarity with thermolysin.
- No significant conformational changes observed in the inhibitor binding site upon lisinopril binding.
Conclusions:
- The solved structure of tACE provides detailed insights into active site interactions and substrate hydrolysis.
- The findings support the rational design of next-generation, domain-selective ACE inhibitors.
- Structural data facilitates understanding of ACE function and inhibitor mechanisms.