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Structure modeling and inhibitor prediction ofNADP oxidoreductase enzyme from Methanobrevibacter smithii.

Sharma A, Chaudhary PP, Sirohi SK, Saxena J - Bioinformation (2011)

Bottom Line: In this work, we first time claim 3D model structure of F420-dependent NADP oxidoreductase enzyme from Methanobrevibacter smithii by comparative homology modeling method.Subsequently, inhibitor prediction study revealed that Lovastatin (-22.07 Kcal/mol) and Compactin (Mevastatin) (-21.91 Kcal/mol) produced more affinity for model structure of NADP oxidoreducatse as compared to F420 (-14.40 Kcal/mol).It indicates that the Lovastatin and Compactin (Mevastatin) compounds (Negative regulator) may act as potential inhibitor of F420 dependent NADP oxidoreducatse protein.

View Article: PubMed Central - PubMed

ABSTRACT
The F420-dependent NADP oxidoreductase enzyme from Methanobrevibacter smithii catalyzes the important electron transfer step during methanogenesis. Therefore, it may act as potential target for blocking the process of methane formation. Its protein sequence is available in GenBank (accession number: ABQ86254.1) however no report has been found about its 3D protein structure. In this work, we first time claim 3D model structure of F420-dependent NADP oxidoreductase enzyme from Methanobrevibacter smithii by comparative homology modeling method. Swiss model and ESyPred3d (via Modeller 6v2) software's were generated the 3D model by detecting 1JAX (A) as template along with sequence identities of 34.272% and 35.40%. Furthermore, PROCHECK with Ramachandran plot and ProSA analysis revealed that swiss model produced better model than Modeller6v2 with 98.90% of residues in favored and additional allowed regions (RM plot) as well as with ProSA Z score of -7.26. In addition, we investigated that the substrate F420 bound at the cavity of the model. Subsequently, inhibitor prediction study revealed that Lovastatin (-22.07 Kcal/mol) and Compactin (Mevastatin) (-21.91 Kcal/mol) produced more affinity for model structure of NADP oxidoreducatse as compared to F420 (-14.40 Kcal/mol). It indicates that the Lovastatin and Compactin (Mevastatin) compounds (Negative regulator) may act as potential inhibitor of F420 dependent NADP oxidoreducatse protein.

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Related in: MedlinePlus

The figure showed (A) Lovastatin inhibitor (pink) binds at the cavity of modeled structure (green) of F420-dependent NADP oxidoreductase protein andresidues surrounding the Lovastatin ligand at 6A0 radius. The residues GLY10, GLY13 THR74 and ILE144 make hydrogen bonds (blue) with Lovastatin. (B)Compactin (Mevastatin) inhibitor (pink) binds at the cavity of modeled structure (green) of F420-dependent NADP oxidoreductase protein and residuessurrounding the Compactin (Mevastatin) ligand at 6A0 radius. The residues GLN12, GLY13, THR74 and ILE144 make hydrogenbonds (blue) with Compactin.
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Figure 6: The figure showed (A) Lovastatin inhibitor (pink) binds at the cavity of modeled structure (green) of F420-dependent NADP oxidoreductase protein andresidues surrounding the Lovastatin ligand at 6A0 radius. The residues GLY10, GLY13 THR74 and ILE144 make hydrogen bonds (blue) with Lovastatin. (B)Compactin (Mevastatin) inhibitor (pink) binds at the cavity of modeled structure (green) of F420-dependent NADP oxidoreductase protein and residuessurrounding the Compactin (Mevastatin) ligand at 6A0 radius. The residues GLN12, GLY13, THR74 and ILE144 make hydrogenbonds (blue) with Compactin.

Mentions: Docking via Patchdock produced higher docking score for Lovastatin (score4852) and Compactin (Mevastatin) (score 4778) along with oxidoreductasenatural ligand F420 (score 6150) (Figure 4). Refined docking (making gridmap on previously predicted active site) also produced lower docking energyfor Lovastatin -22.07 Kcal/mol and Compactin (Mevastatin) -21.91 Kcal/molwhich is much lower then oxidoreducatse natural ligand F420, -14.40 Kcal/mol(Figure 5 & Figure 6). Both the inhibitors bind at the cavity of modeled F420dependent NADP oxidoreducatse protein and show higher affinity as comparedto F420 (Figure 5 & Figure 6). Our research establishes that Lovastatin andCompactin (Mevastatin) may act as potent inhibitor for F420 dependent NADPoxidoreducatse protein in order to block its active site.Based on the matches,we propose the following putative functional role of the target: The target mayparticipate in hydride transfer of DNA photolyase reaction. The N terminal ofthe protein may have dinucleotide binding Rossmann fold domain. The targetmay be a homodimer catalyzing the reversible reduction of NADP+ by the helpof F420H2. It may have NADP binding site at N terminal domain and F420binding at the C terminal domain.


Structure modeling and inhibitor prediction ofNADP oxidoreductase enzyme from Methanobrevibacter smithii.

Sharma A, Chaudhary PP, Sirohi SK, Saxena J - Bioinformation (2011)

The figure showed (A) Lovastatin inhibitor (pink) binds at the cavity of modeled structure (green) of F420-dependent NADP oxidoreductase protein andresidues surrounding the Lovastatin ligand at 6A0 radius. The residues GLY10, GLY13 THR74 and ILE144 make hydrogen bonds (blue) with Lovastatin. (B)Compactin (Mevastatin) inhibitor (pink) binds at the cavity of modeled structure (green) of F420-dependent NADP oxidoreductase protein and residuessurrounding the Compactin (Mevastatin) ligand at 6A0 radius. The residues GLN12, GLY13, THR74 and ILE144 make hydrogenbonds (blue) with Compactin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: The figure showed (A) Lovastatin inhibitor (pink) binds at the cavity of modeled structure (green) of F420-dependent NADP oxidoreductase protein andresidues surrounding the Lovastatin ligand at 6A0 radius. The residues GLY10, GLY13 THR74 and ILE144 make hydrogen bonds (blue) with Lovastatin. (B)Compactin (Mevastatin) inhibitor (pink) binds at the cavity of modeled structure (green) of F420-dependent NADP oxidoreductase protein and residuessurrounding the Compactin (Mevastatin) ligand at 6A0 radius. The residues GLN12, GLY13, THR74 and ILE144 make hydrogenbonds (blue) with Compactin.
Mentions: Docking via Patchdock produced higher docking score for Lovastatin (score4852) and Compactin (Mevastatin) (score 4778) along with oxidoreductasenatural ligand F420 (score 6150) (Figure 4). Refined docking (making gridmap on previously predicted active site) also produced lower docking energyfor Lovastatin -22.07 Kcal/mol and Compactin (Mevastatin) -21.91 Kcal/molwhich is much lower then oxidoreducatse natural ligand F420, -14.40 Kcal/mol(Figure 5 & Figure 6). Both the inhibitors bind at the cavity of modeled F420dependent NADP oxidoreducatse protein and show higher affinity as comparedto F420 (Figure 5 & Figure 6). Our research establishes that Lovastatin andCompactin (Mevastatin) may act as potent inhibitor for F420 dependent NADPoxidoreducatse protein in order to block its active site.Based on the matches,we propose the following putative functional role of the target: The target mayparticipate in hydride transfer of DNA photolyase reaction. The N terminal ofthe protein may have dinucleotide binding Rossmann fold domain. The targetmay be a homodimer catalyzing the reversible reduction of NADP+ by the helpof F420H2. It may have NADP binding site at N terminal domain and F420binding at the C terminal domain.

Bottom Line: In this work, we first time claim 3D model structure of F420-dependent NADP oxidoreductase enzyme from Methanobrevibacter smithii by comparative homology modeling method.Subsequently, inhibitor prediction study revealed that Lovastatin (-22.07 Kcal/mol) and Compactin (Mevastatin) (-21.91 Kcal/mol) produced more affinity for model structure of NADP oxidoreducatse as compared to F420 (-14.40 Kcal/mol).It indicates that the Lovastatin and Compactin (Mevastatin) compounds (Negative regulator) may act as potential inhibitor of F420 dependent NADP oxidoreducatse protein.

View Article: PubMed Central - PubMed

ABSTRACT
The F420-dependent NADP oxidoreductase enzyme from Methanobrevibacter smithii catalyzes the important electron transfer step during methanogenesis. Therefore, it may act as potential target for blocking the process of methane formation. Its protein sequence is available in GenBank (accession number: ABQ86254.1) however no report has been found about its 3D protein structure. In this work, we first time claim 3D model structure of F420-dependent NADP oxidoreductase enzyme from Methanobrevibacter smithii by comparative homology modeling method. Swiss model and ESyPred3d (via Modeller 6v2) software's were generated the 3D model by detecting 1JAX (A) as template along with sequence identities of 34.272% and 35.40%. Furthermore, PROCHECK with Ramachandran plot and ProSA analysis revealed that swiss model produced better model than Modeller6v2 with 98.90% of residues in favored and additional allowed regions (RM plot) as well as with ProSA Z score of -7.26. In addition, we investigated that the substrate F420 bound at the cavity of the model. Subsequently, inhibitor prediction study revealed that Lovastatin (-22.07 Kcal/mol) and Compactin (Mevastatin) (-21.91 Kcal/mol) produced more affinity for model structure of NADP oxidoreducatse as compared to F420 (-14.40 Kcal/mol). It indicates that the Lovastatin and Compactin (Mevastatin) compounds (Negative regulator) may act as potential inhibitor of F420 dependent NADP oxidoreducatse protein.

No MeSH data available.


Related in: MedlinePlus