Homology modeling, molecular dynamics and QM/MM study of the regulatory protein PhoP from Corynebacterium pseudotuberculosis

Moraes, Gleiciane Leal; Azevedo, Vasco; Costa, Marcília Pinheiro da; Miyoshi, Anderson; Silva, Artur M. S.; Silva, Vivian da; Oliveira, Daniel; Teixeira, Maria Fátima da Silva; Lameira, Jerônimo; Alves, Cláudio Nahum

doi:10.1007/s00894-011-1145-x

Cited by 8 publications

(8 citation statements)

References 31 publications

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“…Recently, we have used homology modeling, molecular docking and Molecular Dynamics (MD) simulations to study different biomolecular systems [45]–[47]. In this report, we propose a complete 3D model of HIV Vif by the ab initio approach.…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis of Viral Infectivity Factor of HIV Type 1 and Its Interaction with A3G, EloC and EloB

et al. 2014

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BackgroundThe virion infectivity factor (Vif) is an accessory protein, which is essential for HIV replication in host cells. Vif neutralizes the antiviral host protein APOBEC3 through recruitment of the E3 ubiquitin ligase complex.MethodologyFifty thousand Vif models were generated using the ab initio relax protocol of the Rosetta algorithm from sets of three- and nine-residue fragments using the fragment Monte Carlo insertion-simulated annealing strategy, which favors protein-like features, followed by an all-atom refinement. In the protocol, a constraints archive was used to define the spatial relationship between the side chains from Cys/His residues and zinc ions that formed the zinc-finger motif that is essential for Vif function. We also performed centroids analysis and structural analysis with respect to the formation of the zinc-finger, and the residue disposal in the protein binding domains. Additionally, molecular docking was used to explore details of Vif-A3G and Vif-EloBC interactions. Furthermore, molecular dynamics simulation was used to evaluate the stability of the complexes Vif-EloBC-A3G and Vif-EloC.Principal FindingsThe zinc in the HCCH domain significantly alters the folding of Vif and changes the structural dynamics of the HCCH region. Ab initio modeling indicated that the Vif zinc-finger possibly displays tetrahedral geometry as suggested by Mehle et al. (2006). Our model also showed that the residues L146 and L149 of the BC-box motif bind to EloC by hydrophobic interactions, and the residue P162 of the PPLP motif is important to EloB binding.Conclusions/SignificanceThe model presented here is the first complete three-dimensional structure of the Vif. The interaction of Vif with the A3G protein and the EloBC complex is in agreement with empirical data that is currently available in the literature and could therefore provide valuable structural information for advances in rational drug design.

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Section: Introductionmentioning

confidence: 99%

Structural Analysis of Viral Infectivity Factor of HIV Type 1 and Its Interaction with A3G, EloC and EloB

et al. 2014

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“…10. It has been reported that the aspartate receptor of the activation signal is View Article Online the Asp59 residue (phosphorylation is absolutely conserved) 26 that is located at the N-terminal receiver domain of the response regulator of the PhoP protein, which along with Asp15 has an important role in Mg +2 binding. It has already been established experimentally that this compound possesses antibacterial activity.…”

Section: Active Site Residues Identification and Docking Analysismentioning

confidence: 99%

C. pseudotuberculosis Phop confers virulence and may be targeted by natural compounds

et al. 2014

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The bacterial two-component system (TCS) regulates genes that are crucial for virulence in several pathogens. One of such TCS, the PhoPR system, consisting of a transmembrane sensory histidine kinase protein (PhoR) and an intracellular response regulator protein (PhoP), has been reported to have a major role in mycobacterial pathogenesis. We knocked out the phoP in C. pseudotuberculosis, the causal organism of caseous lymphadenitis (CLA), and using a combination of in vitro and in vivo mouse system, we showed for the first time, that the PhoP of C. pseudotuberculosis plays an important role in the virulence and pathogenicity of this bacterium. Furthermore, we modeled the PhoP of C. pseudotuberculosis and our docking results showed that several natural compounds including Rhein, an anthraquinone from Rheum undulatum, and some drug-like molecules may target PhoP to inhibit the TCS of C. pseudotuberculosis, and therefore may facilitate a remarkable attenuation of bacterial pathogenicity being the CLA. Experiments are currently underway to validate these in silico docking results.

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“…Recently, we have used homology modelling to determine 3D structure of the regulatory response protein (PhoP) of Corynebacterium pseudotuberculosis [10], sialidases from Trypanosoma brucei and Trypanosoma evansi [11] and O-glycoprotein 2-acetamino-2-deoxy-β-D-glucopyranosidase [12]. Herein, we have used homology modelling [9] to describe the 3D structure of the enzymes involved in cytoplasmic steps of biosynthesis of peptidoglycan, namely GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF.…”

Section: Introductionmentioning

confidence: 99%

Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development

et al. 2015

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SUMMARY Tuberculosis (TB) is the second leading cause of human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis (M. tuberculosis), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB.

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Homology modeling, molecular dynamics and QM/MM study of the regulatory protein PhoP from Corynebacterium pseudotuberculosis

Cited by 8 publications

References 31 publications

Structural Analysis of Viral Infectivity Factor of HIV Type 1 and Its Interaction with A3G, EloC and EloB

Structural Analysis of Viral Infectivity Factor of HIV Type 1 and Its Interaction with A3G, EloC and EloB

C. pseudotuberculosis Phop confers virulence and may be targeted by natural compounds

Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development

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