Molecular modeling of Helicobacter pylori arginase and the inhibitor coordination interactions

Azizian, Homa; Bahrami, Homayoon; Pasalar, Parvin; Amanlou, Massoud

doi:10.1016/j.jmgm.2009.12.007

Cited by 36 publications

(24 citation statements)

References 40 publications

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“…The energy-minimized average structure extracted from MD trajectory can be used to design new inhibitors or to identify a new binding site that could be useful in drug discovery [70]. Therefore, we computed the average structure from the MD simulations, which was then further energy minimized and validated by ProSA-web (Z-score of −6.63) ( Table 1).…”

Section: Simulationsmentioning

confidence: 99%

Molecular dynamics simulations of the Bcl-2 protein to predict the structure of its unordered flexible loop domain

2011

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B-cell lymphoma (Bcl-2) protein is an anti-apoptotic member of the Bcl-2 family. It is functionally demarcated into four Bcl-2 homology (BH) domains: BH1, BH2, BH3, BH4, one flexible loop domain (FLD), a transmembrane domain (TM), and an X domain. Bcl-2's BH domains have clearly been elucidated from a structural perspective, whereas the conformation of FLD has not yet been predicted, despite its important role in regulating apoptosis through its interactions with JNK-1, PKC, PP2A phosphatase, caspase 3, MAP kinase, ubiquitin, PS1, and FKBP38. Many important residues that regulate Bcl-2 anti-apoptotic activity are present in this domain, for example Asp34, Thr56, Thr69, Ser70, Thr74, and Ser87. The structural elucidation of the FLD would likely help in attempts to accurately predict the effect of mutating these residues on the overall structure of the protein and the interactions of other proteins in this domain. Therefore, we have generated an increased quality model of the Bcl-2 protein including the FLD through modeling. Further, molecular dynamics (MD) simulations were used for FLD optimization, to predict the flexibility, and to determine the stability of the folded FLD. In addition, essential dynamics (ED) was used to predict the collective motions and the essential subspace relevant to Bcl-2 protein function. The predicted average structure and ensemble of MD-simulated structures were submitted to the Protein Model Database (PMDB), and the Bcl-2 structures obtained exhibited enhanced quality. This study should help to elucidate the structural basis for Bcl-2 anti-apoptotic activity regulation through its binding to other proteins via the FLD.

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Section: Simulationsmentioning

confidence: 99%

Molecular dynamics simulations of the Bcl-2 protein to predict the structure of its unordered flexible loop domain

2011

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“…Nevertheless, all these data show that the amount of dimer decreases with increasing concentrations of salt indicating that electrostatic interactions play important role in dimerization of the protein. The 3D structure of the H. pylori enzyme is not yet known but the model structure has been recently reported (29). An examination of the model structure revealed that the active site residues are conserved.…”

Section: Dimerization and Salt-dependent Activity Assaymentioning

confidence: 99%

“…This suggests that a residue of pK a 9.4 must be involved during the catalysis for both Co 21 -and Mn 21 -arginases. As discussed earlier, the X-ray crystal structure of the H. pylori enzyme is not yet known but a model structure is recently reported (29). An examination of the active site of the model structure of the H. pylori enzyme as well as the reported structures of other arginases suggest that no lysine or cysteine is found at the active site of the enzyme (the pK a of a free cysteine and lysine is 8.4 and 10.6, respectively).…”

Section: Ph-dependent Studiesmentioning

confidence: 99%

Biochemical studies on Helicobacter pylori arginase: Insight into the difference in activity compared to other arginases

Srivastava

2010

IUBMB Life

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SummaryArginase is a binuclear Mn 21 -metalloenzyme of urea cycle that catalyzes the conversion of L-arginine to L-ornithine and urea. Unlike other arginases, the Helicobacter pylori enzyme is selective for Co 21 , and has lower catalytic activity. To understand the differences in the biochemical properties as well as activity compared to other arginases, we carried out a detailed investigation of different metal reconstituted H. pylori arginases that includes steady-state kinetics, fluorescence measurement, pH-dependent and oligomerization assays. Unlike other arginases (except human at physiological pH), the Co 21 -and Mn 21 -reconstituted H. pylori enzymes exhibit cooperative mechanism of arginine hydrolysis, and undergo self-association and activation with increasing concentrations. Analytical gel-filtration assays in conjunction with the kinetic data showed that the protein exists as a mixture of monomer and dimer with monomer being the major form (other arginases exclusively exist as a trimer or hexamer) but the dimer is associated with higher catalytic activity. The proportion of dimer is found to decrease with increasing salt concentrations indicating that salt bridges play important roles in dimerization of the protein. Furthermore, the fluorescence measurement showed that Co 21 ions play an important role in the local tertiary structure of the protein than Mn 21 . This is consistent with the pH-dependent studies where the Co 21 -enzyme showed a single ionization compared to the double in the Mn 21 -enzyme. Thus, this study presents the detailed biochemical and spectroscopic investigations into the differences in the biochemical properties and activity between H. pylori and other arginases.

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“…Root Mean Square Deviation (RMSD) value of the predicted poses to experimentally verified pose is calculated following docking experiment. As RMSD value indicates the measure of spatial similarity between two structures, the prediction of binding mode is considered as successful if the RMSD value is typically found to be less than 2.00 Å [53]. To obtain grid file, Auto-grid program was utilized.…”

Section: Testing Validity Of Autodock 42 and Virtual Screeningmentioning

confidence: 99%

Flavonoids as a scaffold for development of novel anti-angiogenic agents: An experimental and computational enquiry

Gacche

Meshram

Shegokar

et al. 2015

Archives of Biochemistry and Biophysics

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Molecular modeling of Helicobacter pylori arginase and the inhibitor coordination interactions

Cited by 36 publications

References 40 publications

Molecular dynamics simulations of the Bcl-2 protein to predict the structure of its unordered flexible loop domain

Molecular dynamics simulations of the Bcl-2 protein to predict the structure of its unordered flexible loop domain

Biochemical studies on Helicobacter pylori arginase: Insight into the difference in activity compared to other arginases

Flavonoids as a scaffold for development of novel anti-angiogenic agents: An experimental and computational enquiry

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