Cellular and Molecular Life Sciences CMLS

, Volume 61, Issue 21, pp 2677–2686

What’s new in the renin-angiotensin system?

Structure of angiotensin I-converting enzyme
  • E. D. Sturrock
  • R. Natesh
  • J. M. van Rooyen
  • K. R. Acharya
Multi-author Review

DOI: 10.1007/s00018-004-4239-0

Cite this article as:
Sturrock, E.D., Natesh, R., van Rooyen, J.M. et al. CMLS, Cell. Mol. Life Sci. (2004) 61: 2677. doi:10.1007/s00018-004-4239-0

Abstract.

Angiotensin-converting enzyme (ACE) is a zinc- and chloride-dependent metallopeptidase that plays a vital role in the metabolism of biologically active peptides. Until recently, much of the inhibitor design and mechanism of action of this ubiquitous enzyme was based on the structures of carboxypeptidase A and thermolysin. When compared to the recently solved structures of the testis isoform of ACE (tACE) and its Drosophila homologue (AnCE), carboxypeptidase A showed little structural homology outside of the active site, while thermolysin revealed significant but less marked overall similarity. The ellipsoid-shaped structure of tACE, which has a preponderance of α-helices, is characterised by a core channel that has a constriction approximately 10 Å from its opening where the zinc-binding active site is located. Comparison of the native protein with the inhibitor-bound form (lisinopril-tACE) does not reveal any striking differences in the conformation of the inhibitor binding site, disfavouring an open and closed configuration. However, the inhibitor complex does provide insights into the network of hydrogen-bonding and ionic interactions in the active site as well as the mechanism of ACE substrate hydrolysis. The three-dimensional structure of ACE now paves the way for the rational design of a new generation of domain-selective ACE inhibitors.

Key words.

Metallopeptidaseangiotensin I-converting enzymeDrosophila angiotensin converting enzyme homologueneurolysinPyrococcus furiosus carboxypeptidasestructure-based drug design

Copyright information

© Birkhäuser Verlag, Basel 2004

Authors and Affiliations

  • E. D. Sturrock
    • 1
  • R. Natesh
    • 2
  • J. M. van Rooyen
    • 1
  • K. R. Acharya
    • 2
  1. 1.Division of Medical Biochemistry, Faculty of Health SciencesUniversity of Cape TownObservatory, Cape TownSouth Africa
  2. 2.Department of Biology and BiochemistryUniversity of BathClaverton Down, BathUnited Kingdom