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Crystal structures of angiotensin-converting enzyme from Anopheles gambiae in its native form and with a bound inhibitor.
- Source :
-
The Biochemical journal [Biochem J] 2019 Nov 29; Vol. 476 (22), pp. 3505-3520. - Publication Year :
- 2019
-
Abstract
- The mosquitoes of the Anopheles and Aedes genus are some of the most deadly insects to humans because of their effectiveness as vectors of malaria and a range of arboviruses, including yellow fever, dengue, chikungunya, West Nile and Zika. The use of insecticides from different chemical classes is a key component of the integrated strategy against An. gambiae and Ae. aegypti, but the problem of insecticide resistance means that new compounds with different modes of action are urgently needed to replace chemicals that fail to control resistant mosquito populations. We have previously shown that feeding inhibitors of peptidyl dipeptidase A to both An. gambiae and Ae. aegypti mosquito larvae lead to stunted growth and mortality. However, these compounds were designed to inhibit the mammalian form of the enzyme (angiotensin-converting enzyme, ACE) and hence can have lower potency and lack selectivity as inhibitors of the insect peptidase. Thus, for the development of inhibitors of practical value in killing mosquito larvae, it is important to design new compounds that are both potent and highly selective. Here, we report the first structures of AnoACE2 from An. gambiae in its native form and with a bound human ACE inhibitor fosinoprilat. A comparison of these structures with human ACE (sACE) and an insect ACE homologue from Drosophila melanogaster (AnCE) revealed that the AnoACE2 structure is more similar to AnCE. In addition, important elements that differ in these structures provide information that could potentially be utilised in the design of chemical leads for selective mosquitocide development.<br /> (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Subjects :
- Aedes chemistry
Aedes enzymology
Aedes genetics
Animals
Anopheles chemistry
Anopheles genetics
Anopheles growth & development
Drosophila melanogaster chemistry
Drosophila melanogaster enzymology
Fosinopril analogs & derivatives
Fosinopril chemistry
Humans
Insect Proteins antagonists & inhibitors
Insect Proteins genetics
Insect Proteins metabolism
Insecticides chemistry
Larva chemistry
Larva enzymology
Larva genetics
Larva growth & development
Models, Molecular
Peptidyl-Dipeptidase A genetics
Peptidyl-Dipeptidase A metabolism
Angiotensin-Converting Enzyme Inhibitors chemistry
Anopheles enzymology
Insect Proteins chemistry
Peptidyl-Dipeptidase A chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8728
- Volume :
- 476
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- The Biochemical journal
- Publication Type :
- Academic Journal
- Accession number :
- 31682720
- Full Text :
- https://doi.org/10.1042/BCJ20190635