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Long-range replica exchange molecular dynamics guided drug repurposing against tyrosine kinase PtkA of Mycobacterium tuberculosis.

ABSTRACT: Tuberculosis (TB) is a leading cause of death worldwide and its impact has intensified due to the emergence of multi drug-resistant (MDR) and extensively drug-resistant (XDR) TB strains. Protein phosphorylation plays a vital role in the virulence of Mycobacterium tuberculosis (M.tb) mediated by protein kinases. Protein tyrosine phosphatase A (MptpA) undergoes phosphorylation by a unique tyrosine-specific kinase, protein tyrosine kinase A (PtkA), identified in the M.tb genome. PtkA phosphorylates PtpA on the tyrosine residues at positions 128 and 129, thereby increasing PtpA activity and promoting pathogenicity of MptpA. In the present study, we performed an extensive investigation of the conformational behavior of the intrinsically disordered domain (IDD) of PtkA using replica exchange molecular dynamics simulations. Long-term molecular dynamics (MD) simulations were performed to elucidate the role of IDD on the catalytic activity of kinase core domain (KCD) of PtkA. This was followed by identification of the probable inhibitors of PtkA using drug repurposing to block the PtpA-PtkA interaction. The inhibitory role of IDD on KCD has already been established; however, various analyses conducted in the present study showed that IDDPtkA had a greater inhibitory effect on the catalytic activity of KCDPtkA in the presence of the drugs esculin and inosine pranobex. The binding of drugs to PtkA resulted in formation of stable complexes, indicating that these two drugs are potentially useful as inhibitors of M.tb.

SUBMITTER: Nagpal P

PROVIDER: S-EPMC7064604 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Long-range replica exchange molecular dynamics guided drug repurposing against tyrosine kinase PtkA of Mycobacterium tuberculosis.

Nagpal Priya P Jamal Salma S Singh Hina H Ali Waseem W Tanweer Sana S Sharma Rahul R Grover Abhinav A Grover Sonam S

Scientific reports 20200310 1

Tuberculosis (TB) is a leading cause of death worldwide and its impact has intensified due to the emergence of multi drug-resistant (MDR) and extensively drug-resistant (XDR) TB strains. Protein phosphorylation plays a vital role in the virulence of Mycobacterium tuberculosis (M.tb) mediated by protein kinases. Protein tyrosine phosphatase A (MptpA) undergoes phosphorylation by a unique tyrosine-specific kinase, protein tyrosine kinase A (PtkA), identified in the M.tb genome. PtkA phosphorylates ...[more]

PMID: 32157138

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Project description:UnlabelledIn Bacillus subtilis, biosynthesis of exopolysaccharide (EPS), a key biofilm matrix component, is regulated at the posttranslational level by the bacterial tyrosine kinase (BY-kinase) EpsB. EpsB, in turn, relies on the cognate kinase activator EpsA for activation. A concerted role of a second BY-kinase-kinase activator pair, PtkA and TkmA, respectively in biofilm formation was also indicated in previous studies. However, the exact functions of PtkA and TkmA in biofilm formation remain unclear. In this work, we show that the kinase activator TkmA contributes to biofilm formation largely independently of the cognate kinase, PtkA. We further show that the biofilm defect caused by a ?tkmA mutation can be rescued by complementation by epsA, suggesting a functional overlap between TkmA and EpsA and providing a possible explanation for the role of TkmA in biofilm formation. We also show that the importance of TkmA in biofilm formation depends largely on medium conditions; the biofilm defect of ?tkmA is very severe in the biofilm medium LBGM (lysogenic broth [LB] supplemented with 1% [vol/vol] glycerol and 100 ?M MnSO4) but marginal in another commonly used biofilm medium, MSgg (5 mM potassium phosphate [pH 7.0], MOPS [100 mM morpholinepropanesulfonic acid] [pH 7.0], 2 mM MgCl2, 700 ?M CaCl2, 50 ?M MnCl2, 50 ?M FeCl3, 1 ?M ZnCl2, 2 ?M thiamine, 0.5% glycerol, 0.5% glutamic acid, 50 ?g/ml tryptophan, 50 ?g/ml threonine, and 50 ?g/ml phenylalanine). The molecular basis for the medium dependence is likely due to differential expression of tkmA and epsA in the two different media and complex regulation of these genes by both Spo0A and DegU. Our studies provide genetic evidence for possible cross talk between a BY-kinase activator (TkmA) and a noncognate kinase (EpsB) and an example of how environmental conditions may influence such cross talk in regulating biofilm formation in B. subtilis.ImportanceIn bacteria, biosynthesis of secreted polysaccharides is often regulated by bacterial tyrosine kinases (BY-kinases). BY-kinases, in turn, rely on cognate kinase activators for activation. In this study, we investigated the role of a BY-kinase activator in biofilm formation in Bacillus subtilis. We present evidence that different BY-kinase activators may functionally overlap each other, as well as an example of how activities of the BY-kinase activators may be highly dependent on environmental conditions. Our study broadens the understanding of the complexity of regulation of the BY-kinases/kinase activators and the influence on bacterial cell physiology.

Dataset Information

Long-range replica exchange molecular dynamics guided drug repurposing against tyrosine kinase PtkA of Mycobacterium tuberculosis.

Publications

Long-range replica exchange molecular dynamics guided drug repurposing against tyrosine kinase PtkA of Mycobacterium tuberculosis.

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