Abstract
Angiotensin-1-converting enzyme (ACE) is a zinc-dependent carboxypeptidase of therapeutic interest for the treatment of hypertension, inflammation and fibrosis. It consists of two homologous N and C catalytic domains, nACE and cACE, respectively. Unfortunately, the current clinically available ACE inhibitors produce undesirable side effects due to the nonselective inhibition of these domains. Through structure-based drug design, we previously identified a series of diprolyl-derived inhibitors (SG3, SG15, SG16, SG17 and SG18) in an attempt to specifically target nACE. Only one compound, SG16, possessed significant nACEselectivity. The previously determined 16-nACE crystal structure (nACE:SG16) suggested interactions with Tyr369 (Phe381 in cACE) are responsible for this selectivity. To better understand the molecular basis for the lack of selectivity in the remaining compounds, we have cocrystallised nACE in complex with SG3, SG15, SG17 and SG18 and cACE in complex with SG3, SG15, SG16 and SG18 and determined their structures at high resolution. Apart from the catalytic residues, these structures further highlight the importance of residues distal to the active site that may play an important role in the design of domain-selective inhibitors of ACE.
Original language | English |
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Journal | FEBS Journal |
Early online date | 6 Jan 2025 |
DOIs | |
Publication status | E-pub ahead of print - 6 Jan 2025 |
Data Availability Statement
The atomic coordinates and structure factors of nACE:SG3, nACE:SG15, nACE:SG17, nACE:SG18, cACE:SG3, cACE:SG15, cACE:SG16 and cACE:SG18 complexes have been deposited under accession codes 9GBP, 9GBQ, 9GBR, 9GBS, 9GBM, 9GBN, 9GBOand 9GBL, respectively, in the RCSB Protein Data Bank, www.pdb.org.
Acknowledgements
We thank the beamline scientists on I03, I04 and I04-1 at Diamond Light Source, Didcot, Oxfordshire (UK) for their support during X-ray diffraction data collection as part of the proposals MX17212-29, MX17212-34 MX17212-35, MX17212-48, MX17212-50 MX23269-3 and MX23269-5.Funding
Biotechnology and Biological Sciences Research Council (GrantNumber(s): BB/X001032/1); South African National Research Foundation (GrantNumber(s): 13082029517)
Funders | Funder number |
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Biotechnology and Biological Sciences Research Council | BB/X001032/1 |
Keywords
- X-ray crystallography
- angiotensin-1-converting enzyme
- diprolyl-derived inhibitor
- domain-selectivity
- enzyme structure
- inhibitor binding
- metalloprotease
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology