High-Resolution Crystal Structures of Drosophila melanogaster Angiotensin-Converting Enzyme in Complex with Novel Inhibitors and Antihypertensive Drugs

Akif, M.; Georgiadis, Dimitris; Mahajan, Aman; Dive, Vincent; Sturrock, Edward D.; Isaac, R. Elwyn; Acharya, K. Ravi

doi:10.1016/j.jmb.2010.05.024

Cited by 70 publications

(77 citation statements)

References 45 publications

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“…The water structure in the S 2 subsite differed between A and B, suggesting that the aldehyde oxygen can be on either side because it has no direct interaction with the protein. Hydrogen bond interactions calculated with HBPLUS (32) indicates 12 direct hydrogen bonds (Table 3) between the inhibitor and the protein (in addition to the interaction with the zinc), which is five more than observed for its complex with the Drosophila melanogaster angiotensin-converting enzyme homologue despite the same configuration (37). These bonds have arisen from nine residues: Arg 381 , Tyr 369 , and Ala 334 in the S 2 subsite; Tyr 501 with the phosphate; His 331 and His 491 in the S 1 ′ subsite; and Tyr 498 , His 491 , and Gln 259 in the S 2 ′ subsite (Fig.…”

Section: Resultsmentioning

confidence: 96%

The N Domain of Human Angiotensin-I-converting Enzyme

Anthony

Corradi

Schwager

et al. 2010

Journal of Biological Chemistry

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Angiotensin-I-converting enzyme (ACE) plays a critical role in the regulation of blood pressure through its central role in the renin-angiotensin and kallikrein-kinin systems. ACE contains two domains, the N and C domains, both of which are heavily glycosylated. Structural studies of ACE have been fraught with severe difficulties because of surface glycosylation of the protein. In order to investigate the role of glycosylation in the N domain and to create suitable forms for crystallization, we have investigated the importance of the 10 potential N-linked glycan sites using enzymatic deglycosylation, limited proteolysis, and mass spectrometry. A number of glycosylation mutants were generated via site-directed mutagenesis, expressed in CHO cells, and analyzed for enzymatic activity and thermal stability. At least eight of 10 of the potential glycan sites are glycosylated; three C-terminal sites were sufficient for expression of active N domain, whereas two N-terminal sites are important for its thermal stability. The minimally glycosylated Ndom389 construct was highly suitable for crystallization studies. The structure in the presence of an N domain-selective phosphinic inhibitor RXP407 was determined to 2.0 Å resolution. The Ndom389 structure revealed a hinge region that may contribute to the breathing motion proposed for substrate binding.

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Section: Resultsmentioning

confidence: 96%

The N Domain of Human Angiotensin-I-converting Enzyme

Anthony

Corradi

Schwager

et al. 2010

Journal of Biological Chemistry

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“…Homology models for AnoACE2 and AnoACE3 were prepared using SWISS-MODEL464748 with the crystal structure of Drosophila melanogaster ACE homologue (also known as AnCE) (PDB code 2 × 8Y)) used as the template (Fig. 5)49.…”

Section: Resultsmentioning

confidence: 99%

“…Our extensive knowledge from high resolution structural studies on how inhibitors interact with both the N- and C-domains of human ACE and insect ACE2549505152535455565758 has revealed the molecular basis of binding features of the inhibitors and highlights differences in the inhibitor-enzyme interaction of insect ACE compared with the active sites of the human enzyme. Using the AnoACE homology models and amino acid sequence alignment, it is possible to compare different ACE proteins to look for residue and environment differences in both AnoACE2 and AnoACE3, which could be targeted to create specific inhibitors against these enzymes.…”

Section: Resultsmentioning

confidence: 99%

The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae

Hasan

Williams

Ismail

et al. 2017

Sci Rep

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The control of mosquitoes is threatened by the appearance of insecticide resistance and therefore new control chemicals are urgently required. Here we show that inhibitors of mosquito peptidyl dipeptidase, a peptidase related to mammalian angiotensin-converting enzyme (ACE), are insecticidal to larvae of the mosquitoes, Aedes aegypti and Anopheles gambiae. ACE inhibitors (captopril, fosinopril and fosinoprilat) and two peptides (trypsin-modulating oostatic factor/TMOF and a bradykinin-potentiating peptide, BPP-12b) were all inhibitors of the larval ACE activity of both mosquitoes. Two inhibitors, captopril and fosinopril (a pro-drug ester of fosinoprilat), were tested for larvicidal activity. Within 24 h captopril had killed >90% of the early instars of both species with 3rd instars showing greater resistance. Mortality was also high within 24 h of exposure of 1st, 2nd and 3rd instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1st instars appeared to be less susceptible to this pro-drug even after 72 h exposure. Homology models of the larval An. gambiae ACE proteins (AnoACE2 and AnoACE3) reveal structural differences compared to human ACE, suggesting that structure-based drug design offers a fruitful approach to the development of selective inhibitors of mosquito ACE enzymes as novel larvicides.

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“…Interestingly, we note that some experimental evidence suggested that the absence of Cl − (II) in the ACE homologue from Drosophila melanogaster , AnCE, does not seem to affect the binding of small molecule inhibitors, such as lisnopril and enalaprilat. 16, 66 So it is possible that its effect is more pronounced for long chain substrates.…”

Section: Discussionmentioning

confidence: 99%

Inhibitor and Substrate Binding by Angiotensin-Converting Enzyme: Quantum Mechanical/Molecular Mechanical Molecular Dynamics Studies

Wang

et al. 2011

J. Chem. Inf. Model.

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Angiotensin-converting enzyme (ACE) is an important zinc-dependent hydrolase responsible for converting the inactive angiotensin I to the vasoconstrictor angiotensin II and for inactivating the vasodilator bradykinin. However, the substrate binding mode of ACE has not been completely understood. In this work, we propose a model for an ACE Michaelis complex based on two known X-ray structures of inhibitor-enzyme complexes. Specifically, the human testis angiotensin-converting enzyme (tACE) complexed with two clinic drugs were first investigated using a combined quantum mechanical and molecular mechanical (QM/MM) approach. The structural parameters obtained from the 550 ps molecular dynamics simulations are in excellent agreement with the X-ray structures, validating the QM/MM approach. Based on these structures, a model for the Michaelis complex was proposed and simulated using the same computational protocol. Implications to ACE catalysis are discussed.

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High-Resolution Crystal Structures of Drosophila melanogaster Angiotensin-Converting Enzyme in Complex with Novel Inhibitors and Antihypertensive Drugs

Cited by 70 publications

References 45 publications

The N Domain of Human Angiotensin-I-converting Enzyme

The N Domain of Human Angiotensin-I-converting Enzyme

The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae

Inhibitor and Substrate Binding by Angiotensin-Converting Enzyme: Quantum Mechanical/Molecular Mechanical Molecular Dynamics Studies

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