Structure of human Endothelin-converting Enzyme I Complexed with Phosphoramidon

Schulz, Henk; Dale, Glenn E.; Karimi-Nejad, Yasmin; Oefner, Christian

doi:10.1016/j.jmb.2008.10.052

Cited by 45 publications

(61 citation statements)

References 62 publications

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“…7 ). Thus, zinc has been found in tetrahedral geometry with His 433, His 437, Glu 461, carbonyl oxygen of Asp 7 of Aβ peptide and one water molecule similar to earlier reports [Patel et al, 2007;Schulz et al, 2009].…”

Section: Zinc Ion Interactions During MD Simulationsupporting

confidence: 85%

Evaluation of a Possible Role of Stigmatella aurantiaca ACE in Aβ Peptide Degradation: A Molecular Modeling Approach

Jalkute¹,

Sonawane²

2015

Microb Physiol

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Amyloid-β (Aβ)-degrading enzymes are known to degrade Aβ peptides, a causative agent of Alzheimer's disease. These enzymes are responsible for maintaining Aβ concentration. However, loss of such enzymes or their Aβ-degrading activity because of certain genetic as well as nongenetic reasons initiates the accumulation of Aβ peptides in the human brain. Considering the limitations of the human enzymes in clearing Aβ peptide, the search for microbial enzymes that could cleave Aβ is necessary. Hence, we built a three-dimensional model of angiotensin-converting enzyme (ACE) from Stigmatella aurantiaca using homology modeling technique. Molecular docking and molecular dynamics simulation techniques were used to outline the possible cleavage mechanism of Aβ peptide. These findings suggest that catalytic residue Glu 434 of the model could play a crucial role to degrade Aβ peptide between Asp 7 and Ser 8. Thus, ACE from S. aurantiaca might cleave Aβ peptides similar to human ACE and could be used to design new therapeutic strategies against Alzheimer's disease.

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Section: Zinc Ion Interactions During MD Simulationsupporting

confidence: 85%

Evaluation of a Possible Role of Stigmatella aurantiaca ACE in Aβ Peptide Degradation: A Molecular Modeling Approach

Jalkute¹,

Sonawane²

2015

Microb Physiol

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“…Our structural data reveal a significant structural conservation with human zinc-dependent metalloproteases NEP (24) and ECE-1 (25), thus identifying M. tuberculosis Zmp1 as a new member of M13 Zn-dependent metalloproteases. However, subtle differences are present in the catalytic site of Zmp1 that could be exploited for the design of specific inhibitors against the mycobacterial enzyme.…”

mentioning

confidence: 75%

Crystal Structure of Mycobacterium tuberculosis Zinc-dependent Metalloprotease-1 (Zmp1), a Metalloprotease Involved in Pathogenicity

Ferraris

Sbardella

Petrera

et al. 2011

Journal of Biological Chemistry

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Mycobacterium tuberculosis, the causative agent of tuberculosis, parasitizes host macrophages. The resistance of the tubercle bacilli to the macrophage hostile environment relates to their ability to impair phagosome maturation and its fusion with the lysosome, thus preventing the formation of the phago-lysosome and eventually arresting the process of phagocytosis. The M. tuberculosis zinc-dependent metalloprotease Zmp1 has been proposed to play a key role in the process of phagosome maturation inhibition and emerged as an important player in pathogenesis. Here, we report the crystal structure of wild-type Zmp1 at 2.6 Å resolution in complex with the generic zinc metalloprotease inhibitor phosphoramidon, which we demonstrated to inhibit the enzyme potently. Our data represent the first structural characterization of a bacterial member of the zinc-dependent M13 endopeptidase family and revealed a significant degree of conservation with eukaryotic enzymes. However, structural comparison of the Zmp1-phosphoramidon complex with homologous human proteins neprilysin and endothelinconverting enzyme-1 revealed unique features of the Zmp1 active site to be exploited for the rational design of specific inhibitors that may prove useful as a pharmacological tool for better understanding Zmp1 biological function.

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“…MVD performs flexible ligand docking, so the optimal geometry of the ligand will be determined during the docking. The MolDock [48] scoring function (MolDock Score) used by MVD is derived from the PLP scoring functions originally proposed by Gehlhaar et al and later extended by Yang et al [49]. The MolDock scoring function further improves these scoring functions with a new hydrogen bonding term and new charge schemes.…”

Section: The Simulation Detailsmentioning

confidence: 99%

Docking Studies on Cyclooxygenases-2 Inhibitors based On Potential Ligand Binding Sites

Nekkaz¹,

Daoud²,

Younes³

et al. 2014

IJCA

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In the last years, the development of the drug for the treatment of inflammation is very fast. The inflammation is a first-rate example of a disease that symbolizes turmoil in normal host defense systems. COX-2 is an oxido-reductase having a role in prostaglandin biosynthesis, inflammatory responses and in cardiovascular events. COX-2 has gained special focus on research since past few decades. The compounds isolated from plants have good inhibitory effects against cyclooxygenase.In this study, Molecular modeling and docking analysis were used to predict and understand interactions between COX-2 and some compounds isolated from Artemisia arborescensL. The approach is applicable in engineering 3D structures of enzymatic models, and studying interactions of active site residues with ligands show that the three compounds: L 9, L 8 and L 4 give the best results, so they may be effective as the potential inhibitor compound against COX-2 protein and can be evaluated as anti-inflammatory drug molecule using clinical trials.

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Structure of human Endothelin-converting Enzyme I Complexed with Phosphoramidon

Cited by 45 publications

References 62 publications

Evaluation of a Possible Role of <b><i>Stigmatella aurantiaca</i></b> ACE in Aβ Peptide Degradation: A Molecular Modeling Approach

Evaluation of a Possible Role of <b><i>Stigmatella aurantiaca</i></b> ACE in Aβ Peptide Degradation: A Molecular Modeling Approach

Crystal Structure of Mycobacterium tuberculosis Zinc-dependent Metalloprotease-1 (Zmp1), a Metalloprotease Involved in Pathogenicity

Docking Studies on Cyclooxygenases-2 Inhibitors based On Potential Ligand Binding Sites

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