Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Highlight
  • Published:

Structure-based drug design

An ACE surprise

Nature Reviews Drug Discovery volume 2, page 252 (2003)Cite this article

Now, Acharya and colleagues have filled in the missing gaps in our knowledge by determining the X-ray structure of ACE, and its complex with the widely used ACE inhibitor lisinopril, at high resolution. There are two isoforms of ACE (somatic and testicular), but the authors looked at the shorter testicular version, which contains a carboxy-terminal (C) domain (the somatic form contains a C and an amino-terminal (N) domain), as previous evidence suggested that the C domain is the dominant functional site.

The three-dimensional structure revealed that ACE in fact bears little resemblance to carboxypeptidase A (except the active site zinc-binding motif). Instead, it resembles rat neurolysin and Pyrococcus furiosus carboxypeptidase, despite sharing little amino-acid-sequence similarity to these two proteins. This similarity extended to the active site, which consists of a deep, narrow channel that divides the molecule into two subdomains. On top of the molecule is an amino-terminal 'lid', which seems to allow only small peptide substrates (25–30 amino acids) access to the active site cleft — this accounts for the inability of ACE to hydrolyse large, folded substrates. Current ACE inhibitors bind to both the C and N domains, so this detailed view of the active site should provide an opportunity to design next-generation, domain-selective ACE inhibitors with the potential for greater efficacy, fewer side effects and new treatment indications.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

References

ORIGINAL RESEARCH PAPER

  1. Natesh, R., Schwager, S. L. U., Sturrock, E. D. & Acharya, K. R. Crystal structure of the human angiotensin-converting enzyme–lisinopril complex. Nature 421, 551–554 (2003)

    Article  CAS  Google Scholar 

FURTHER READING

  1. Zaman, M. A., Oparil, S. & Calhoun, D. A. Drugs targeting the renin–angiotensin–aldosterone system. Nature Rev. Drug Discov. 1, 621–636 (2002)

    Article  CAS  Google Scholar 

Download references

Authors
  1. Simon Frantz
    View author publications

    Search author on:PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frantz, S. An ACE surprise. Nat Rev Drug Discov 2, 252 (2003). https://doi.org/10.1038/nrd1072

Download citation

  • Issue date:

  • DOI: https://doi.org/10.1038/nrd1072

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing