Structural basis for the inhibition of human angiotensin-1 converting enzyme by fosinoprilat

Gyles Cozier, Emma Newby, Sylwa Schwager, Elwyn Isaac, Edward Sturrock, R Acharya

Research output: Contribution to journalArticlepeer-review

4 Citations (SciVal)

Abstract



Human angiotensin I-converting enzyme (ACE) has two isoforms, somatic ACE (sACE) and testis ACE (tACE). The functions of sACE are widespread, with its involvement in blood pressure regulation most extensively studied. sACE is composed of an N-domain (nACE) and a C-domain (cACE), both catalytically active but have significant structural differences, resulting in different substrate specificities. Even though ACE inhibitors are used clinically, they need much improvement because of serious side effects seen in patients (~ 25-30%) with long-term treatment due to nonselective inhibition of nACE and cACE. Investigation into the distinguishing structural features of each domain is therefore of vital importance for the development of domain-specific inhibitors with minimal side effects. Here, we report kinetic data and high-resolution crystal structures of both nACE (1.75 Å) and cACE (1.85 Å) in complex with fosinoprilat, a clinically used inhibitor. These structures allowed detailed analysis of the molecular features conferring domain selectivity by fosinoprilat. Particularly, altered hydrophobic interactions were observed to be a contributing factor. These experimental data contribute to improved understanding of the structural features that dictate ACE inhibitor domain selectivity, allowing further progress towards designing novel 2nd-generation domain-specific potent ACE inhibitors suitable for clinical administration, with a variety of potential future therapeutic benefits. DATABASE: The atomic coordinates and structure factors for nACE-fosinoprilat and cACE-fosinoprilat structures have been deposited with codes 7Z6Z and 7Z70, respectively, in the RCSB Protein Data Bank, www.pdb.org.
Original languageEnglish
Pages (from-to)6659-6671
Number of pages13
JournalFEBS Journal
Volume289
Issue number21
Early online date2 Jun 2022
DOIs
Publication statusPublished - 30 Nov 2022

Bibliographical note

We thank the scientists at stations i03 and i04 (Proposal Number mx17212) of Diamond Light Source, Didcot, Oxfordshire (UK), for their support during X-ray diffraction data collection. This work was supported by the Medical Research Council (U.K.) Research Grant MR/M026647/1 (to K.R.A.) and the National Research Foundation (South Africa) CPRR grant 13082029517 (to E.D.S.).

Keywords

  • X-ray crystallography
  • angiotensin-1-converting enzyme
  • domain selectivity
  • enzyme structure
  • inhibitor binding
  • metalloprotease

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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