Probing the structure-function relationship of Mycobacterium leprae HSP18 under different UV radiations

Chakraborty, Ayon; Nandi, Sandip K.; Panda, Alok Kumar; Mahapatra, Pinaki Prasad; Giri, Sourav Kumar; Biswas, Ashis

doi:10.1016/j.ijbiomac.2018.07.151

Cited by 12 publications

(22 citation statements)

References 73 publications

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“…12 D, Table 4). The estimated T m value (˜61.08 °C) for HSP18 is similar to that of the earlier reports [29, 50,72]. Interestingly, the T m value decreased further for HSP18 pre-incubated with these three MDT drugs, that is, 58.59 °C (HSP18 pre-incubated with 100 μM dapsone), 60.02 °C (HSP18 pre-incubated with 100 μM clofazimine), and 53.26 °C (HSP18 pre-incubated with 100 μM rifampicin), respectively (Fig.…”

Section: Binding Of Mdt Drugs To Hsp18 Alters the Conformations As Well As Lowers The Structural Stability Of Hsp18supporting

confidence: 89%

“…12 C). The elution profile as well as the estimated oligomeric mass of HSP18 (devoid of 6× His tag) in absence of any drug is in good agreement with gel filtration chromatographic results of the same protein as mentioned earlier [29, 72,75]. HSP18 pre-incubated with 100 µM of dapsone or 100 µM of clofazimine was eluted from the column at ˜9.60 and ˜9.27 mL, respectively which correlated to an oligomeric mass of ˜379.6 kDa (˜21 mer; standard error of measurement was 1.2%) and ˜486.2 kDa (˜27 mer; standard error of measurement was 0.8%), respectively (Fig.…”

Section: Binding Of Mdt Drugs To Hsp18 Alters the Conformations As Well As Lowers The Structural Stability Of Hsp18supporting

confidence: 88%

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Interaction of constituents of MDT regimen for leprosy with Mycobacterium leprae HSP18: impact on its structure and function

2021

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Mycobacterium leprae, the causative organism of leprosy, harbors many antigenic proteins, and one such protein is the 18-kDa antigen. This protein belongs to the small heat shock protein family and is commonly known as HSP18. Its chaperone function plays an important role in the growth and survival of M. leprae inside infected hosts. HSP18/18-kDa antigen is often used as a diagnostic marker for determining the efficacy of multidrug therapy (MDT) in leprosy. However, whether MDT drugs (dapsone, clofazimine, and rifampicin) do interact with HSP18 and how these interactions affect its structure and chaperone function is still unclear. Here, we report evidence of HSP18-dapsone/clofazimine/rifampicin interaction and its impact on the structure and chaperone function of HSP18. These three drugs interact efficiently with HSP18 (having submicromolar binding affinity) with 1 : 1 stoichiometry. Binding of these MDT drugs to the 'α-crystallin domain' of HSP18 alters its secondary structure and tryptophan micro-environment. Furthermore, surface hydrophobicity, oligomeric size, and thermostability of the protein are reduced upon interaction with these three drugs. Eventually, all these structural alterations synergistically decrease the chaperone function of HSP18. Interestingly, the effect of rifampicin on the structure, stability, and chaperone function of this mycobacterial small heat shock protein is more pronounced than the other two MDT drugs. This reduction in the chaperone function of HSP18 may additionally abate M. leprae survivability during multidrug treatment. Altogether, this study provides a possible foundation for rational designing and development of suitable HSP18 inhibitors in the context of effective treatment of leprosy.

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Section: Binding Of Mdt Drugs To Hsp18 Alters the Conformations As Well As Lowers The Structural Stability Of Hsp18supporting

confidence: 89%

Section: Binding Of Mdt Drugs To Hsp18 Alters the Conformations As Well As Lowers The Structural Stability Of Hsp18supporting

confidence: 88%

Interaction of constituents of MDT regimen for leprosy with Mycobacterium leprae HSP18: impact on its structure and function

2021

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“…The Mpro from SARS CoV-2 is reported to share more than 96% sequence similarity with the same protease from SARS CoV-1 and MERS which makes it an ideal target for broad-spectrum anti-CoV therapy (Ghosh et al, 2020b). Even more sequence similarity is observed between the main protease from SARS CoV-1 and SARS CoV-2 with a difference in only twelve amino acid residues (Supplemental Figure 1; Sequence homology performed using CLUSTALW (1.83) multiple sequence alignment program (Chakraborty et al, 2018;Nandi et al, 2016)) (Macchiagodena et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Computer aided identification of potential SARS CoV-2 main protease inhibitors from diterpenoids and biflavonoids of Torreya nucifera leaves

Ghosh

Chakraborty

Biswas

et al. 2020

Journal of Biomolecular Structure and Dynamics

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SARS CoV-2 is the causative agent of the pandemic disease COVID-19. There is an urgent need for effective drugs or vaccines which can effectively combat this outbreak. The main protease (Mpro), a key component for the SARS CoV-2 replication, is considered to be one of the important drug targets for developing anti-COVID-19 drugs. This SARS CoV-2 Mpro/cysteine protease has high sequence similarity with the same protease from SARS CoV-1. Previously, it has been shown experimentally that eight diterpenoids and four biflavonoids derived from the leaf of Torreya nucifera show inhibitory effect on the cleavage/catalytic activity of the SARS CoV-1 Mpro. But whether these phytochemicals exhibit any inhibitory effect on SARS CoV-2 Mpro is unclear. To understand this fact, here, we have adopted various in-silico approaches. Diterpenoids and biflavonoids those qualified pharmacological test (hinokiol, amentoflavone, bilobetin and ginkgetin) and two well-known Mpro inhibitors (N3 and lopinavir) were subjected for molecular docking studies. Only three biflavonoids (amentoflavone, bilobetin and ginkgetin) were selected by comparing their binding affinities with N3 and lopinavir. They interacted with two most important catalytic residues of Mpro (His41 and Cys145). Molecular dynamics studies further revealed that these three Mpro-biflavonoid complexes are highly stable and share a similar degree of compactness. Besides, these complexes experience less conformational fluctuations and more expansion than Mpro-N3 and/or Mpro-lopinavir complex. MM-GBSA and H-bond analysis further corroborated these findings. Altogether, our study suggested that these three biflavonoids could possibly inhibit the proteolytic/catalytic activity of SARS CoV-2 Mpro and might be useful for COVID-19 treatment.

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“…Previously, several studies have utilized bacterially expressed purified recombinant proteins to study the effect of UV-B light on the stability and folding/unfolding properties of proteins in vitro [15, 16, 18, 39] and have revealed valuable information on the structure-function aspects of various key regulatory proteins. Since AtMYB4 shows responsiveness to UV-B light [12], we first investigated the biophysical properties of the purified recombinant AtMYB4 in vitro following exposure to UV-B light.…”

Section: Resultsmentioning

confidence: 99%

Investigation of the effect of UV-B light on Arabidopsis MYB4 (AtMYB4) transcription factor stability and detection of a putative MYB4-binding motif in the promoter proximal region of AtMYB4

et al. 2019

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Here, we have investigated the possible effect of UV-B light on the folding/unfolding properties and stability of Arabidopsis thaliana MYB4 (AtMYB4) transcription factor in vitro by using biophysical approaches. Urea-induced equilibrium unfolding analyses have shown relatively higher stability of the wild-type recombinant AtMYB4 protein than the N-terminal deletion forms after UV-B exposure. However, as compared to wild-type form, AtMYB4Δ2 protein, lacking both the two N-terminal MYB domains, showed appreciable alteration in the secondary structure following UV-B exposure. UV-B irradiated AtMYB4Δ2 also displayed higher propensity of aggregation in light scattering experiments, indicating importance of the N-terminal modules in regulating the stability of AtMYB4 under UV-B stress. DNA binding assays have indicated specific binding activity of AtMYB4 to a putative MYB4 binding motif located about 212 bp upstream relative to transcription start site of AtMYB4 gene promoter, while relatively weak DNA binding activity was detected for another putative MYB4 motif located at -908 bp in AtMYB4 promoter. Gel shift and fluorescence anisotropy studies have shown increased binding affinity of UV-B exposed AtMYB4 to the promoter proximal MYB4 motif. ChIP assay has revealed binding of AtMYB4 to the promoter proximal (-212 position) MYB4 motif (ACCAAAC) in vivo . Docking experiments further revealed mechanistic detail of AtMYB4 interaction with the putative binding motifs. Overall, our results have indicated that the N-terminal 62–116 amino acid residues constituting the second MYB domain plays an important role in maintaining the stability of the C-terminal region and the overall stability of the protein, while a promoter proximal MYB-motif in AtMYB4 promoter may involve in the regulation of its own expression under UV-B light.

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Probing the structure-function relationship of Mycobacterium leprae HSP18 under different UV radiations

Cited by 12 publications

References 73 publications

Interaction of constituents of MDT regimen for leprosy with Mycobacterium leprae HSP18: impact on its structure and function

Interaction of constituents of MDT regimen for leprosy with Mycobacterium leprae HSP18: impact on its structure and function

Computer aided identification of potential SARS CoV-2 main protease inhibitors from diterpenoids and biflavonoids of Torreya nucifera leaves

Investigation of the effect of UV-B light on Arabidopsis MYB4 (AtMYB4) transcription factor stability and detection of a putative MYB4-binding motif in the promoter proximal region of AtMYB4

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