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Structural variability of Mycobacterium tuberculosis SSB and susceptibility to inhibition


Affiliations
1 Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560 012, India
2 Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560 012, India; Present address: RIKEN Center for Computational Science, Japan
3 Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560 012, India; Present address: Sitaram Ayurveda Private Limited, Thrissur 680 007, India
4 Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560 012, India; Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru 560 012, India
5 Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560 012, India
 

Single-stranded DNA is formed at various stages of DNA metabolism. It is protected from degradation by single-stranded DNA-binding proteins (SSBs). Structural variability has been observed in the quaternary arrangement of tetrameric SSBs from mycobacteria and other sources. Here we describe two novel crystal forms which illustrate the extent of structural variability. Docking studies carried out with inhibitors identified from DNA-binding assays allowed the characterization of eight distinct potential binding regions or grooves on each tetramer that circumvent structurally variable regions. Compounds known to inhibit certain bacterial SSBs were tested against Mycobacterium tuberculosis SSB (MtSSB) using DNA-binding and cellular assays. We report two compounds that inhibit MtSSB and growth of the bacterium. Together, this structural analysis reveals a strategy to exploit the variability of MtSSB for the design of inhibitors to this protein. The variability in structure of MtSSB could contribute to its susceptibility to inhibition

Keywords

Binding regions, crystal structure, docking, inhibitor development, Mycobacterium tuberculosis, structural plasticity.
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  • Structural variability of Mycobacterium tuberculosis SSB and susceptibility to inhibition

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Authors

Srikalaivani Raja
Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560 012, India
Anju Paul
Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560 012, India
Sriram Raghavan
Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560 012, India; Present address: RIKEN Center for Computational Science, Japan
Sibi Narayanan
Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560 012, India; Present address: Sitaram Ayurveda Private Limited, Thrissur 680 007, India
Somnath Shee
Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560 012, India; Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru 560 012, India
Amit Singh
Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560 012, India; Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru 560 012, India
Umesh Varshney
Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560 012, India
Balasubramanian Gopal
Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560 012, India
Mamannamana Vijayan
Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560 012, India

Abstract


Single-stranded DNA is formed at various stages of DNA metabolism. It is protected from degradation by single-stranded DNA-binding proteins (SSBs). Structural variability has been observed in the quaternary arrangement of tetrameric SSBs from mycobacteria and other sources. Here we describe two novel crystal forms which illustrate the extent of structural variability. Docking studies carried out with inhibitors identified from DNA-binding assays allowed the characterization of eight distinct potential binding regions or grooves on each tetramer that circumvent structurally variable regions. Compounds known to inhibit certain bacterial SSBs were tested against Mycobacterium tuberculosis SSB (MtSSB) using DNA-binding and cellular assays. We report two compounds that inhibit MtSSB and growth of the bacterium. Together, this structural analysis reveals a strategy to exploit the variability of MtSSB for the design of inhibitors to this protein. The variability in structure of MtSSB could contribute to its susceptibility to inhibition

Keywords


Binding regions, crystal structure, docking, inhibitor development, Mycobacterium tuberculosis, structural plasticity.

References





DOI: https://doi.org/10.18520/cs%2Fv122%2Fi3%2F281-289