Crystal structure of histone-like protein from<i>Streptococcus mutans</i>refined to 1.9 Å resolution

O’Neil, Pierce T.; Lovell, Scott; Mehzabeen, N.; Battaile, Kevin P.; Biswas, Indranil

doi:10.1107/s2053230x1600217x

Cited by 7 publications

(6 citation statements)

References 53 publications

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“…The predicted structure of the SpnHU homodimer based on SauHU and SmuHU crystal structures is shown in Figure 1B . This structure in SauHU and SmuHU has a V-like form that is transversally divided in two parts: an α-helical body and two protruding β-ribbon arms, which have a flexible nature and clamp DNA along the minor groove ( Kim et al, 2014 ; O’Neil et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

HU of Streptococcus pneumoniae Is Essential for the Preservation of DNA Supercoiling

et al. 2018

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The histone-like protein HU is a conserved nucleoid-associated protein that is involved in the maintenance of the bacterial chromosome architecture. It is the only known nucleoid-associated protein in Streptococcus pneumoniae, but it has not been studied. The pneumococcal gene encoding this protein, hlp, is shown herein to be essential for cell viability. Its disruption was only possible either when it was duplicated in the chromosome and its expression induced from the PZn promoter, or when hlp was cloned into a plasmid under the control of the inducible Pmal promoter. In vitro assays indicated that pneumococcal HU shows a preference for binding to supercoiled DNA rather than to linear or nicked DNA. In vivo experiments in which the amount of HU was manipulated showed a relationship between the amount of HU and the level of DNA supercoiling. A twofold reduction in the amount of HU triggered a 21% increase in DNA relaxation in untreated cells. However, in cells treated with novobiocin, a drug that relaxes DNA by inhibiting DNA gyrase, a 35% increase in DNA relaxation was observed, instead of the expected 20% in cells with a constitutive HU amount. Conversely, a fourfold HU increase caused only 14% of DNA relaxation in the presence of novobiocin. Taken together, these results support an essential role for HU in the maintenance of DNA supercoiling in S. pneumoniae.

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Section: Resultsmentioning

confidence: 99%

HU of Streptococcus pneumoniae Is Essential for the Preservation of DNA Supercoiling

et al. 2018

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“…It has been reported that some members of DNA-binding proteins are involved in DNA binding, supercoiling and DNA compaction. In addition to architectural roles, some DNA-binding proteins also play regulatory roles in DNA replication and repair, and act as global transcriptional regulators in many bacteria [ 41 ]. Galactose binding protein encoded by the down-regulated M949_RS00790 gene belongs to a group of soluble proteins that can be found in the periplasmic space of Gram-negative bacteria; some members of these proteins are responsible for stimulating chemotaxis in low nutrient environments and participate in active transport of small molecules and ions from the periplasm to the cytoplasm [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Disruption of the M949_RS01915 gene changed the bacterial lipopolysaccharide pattern, pathogenicity and gene expression of Riemerella anatipestifer

Dou

Wang

et al. 2017

Vet Res

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Riemerella anatipestifer is an important pathogen that causes septicemia anserum exsudativa in ducks. Lipopolysaccharide (LPS) is considered to be a major virulence factor of R. anatipestifer. To identify genes involved in LPS biosynthesis, we screened a library of random Tn4351 transposon mutants using a monoclonal antibody against R. anatipestifer serotype 1 LPS (anti-LPS MAb). A mutant strain RA1067 which lost the reactivity in an indirect ELISA was obtained. Southern blot and sequencing analyses indicated a single Tn4351 was inserted at 116 bp in the M949_RS01915 gene in the RA1067 chromosomal DNA. Silver staining and Western blot analyses indicated that the RA1067 LPS was defected compared to the wild-type strain CH3 LPS. The RA1067 displayed a significant decreased growth rate at the late stage of growth in TSB in comparison with CH3. In addition, RA1067 showed higher susceptibility to complement-dependent killing, more than 360-fold attenuated virulence based on the median lethal dose determination, increased bacterial adhesion and invasion capacities to Vero cells and significantly decreased blood bacterial loads in RA1067 infected ducks, when compared to the CH3. An animal experiment indicated that inactivated RA1067 cells was effective in cross-protecting of the ducks from challenging with R. anatipestifer strains WJ4 (serotype 1), Yb2 (serotype 2) and HXb2 (serotype 10), further confirming the alteration of the RA1067 antigenicity. Moreover, RNA-Seq analysis and real-time PCR verified two up-regulated and three down-regulated genes in RA1067. Our findings demonstrate that the M949_RS01915 gene is associated to bacterial antigenicity, pathogenicity and gene regulation of R. anatipestifer.

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“…HLPs are one such essential NAPs produced by S. mutans. The essentiality of streptococcal HLPs for survival makes it an ideal target for the development of drug for controlling streptococcal infections [15].…”

Section: Discussionmentioning

confidence: 99%

“…One of the studies on crystallization of S. mutans HLP has compared it to HLP from M. tuberculosis called Mtb HU (15). In spite of evolutionary divergence based on sequence, SmHLP is structurally similar to HLP from M. tuberculosis.…”

Section: Discussionmentioning

confidence: 99%

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In Silico Drug Repurposing to Target Histone-Like Protein of Streptococcus Mutans

Marimuthu¹,

Rosy²,

Thangamariappan³

et al. 2019

IJEAT

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Streptococcus mutans, in spite of its natural occurrence in human oral cavity, causes dental caries and rarely, in some complications, infective endocarditis. Development of vaccines or drugs to prevent or control these organisms has been under study. Histone-like protein (HLP), a nucleoid associated protein, is found essential for the survival and virulence of these pathogens. We have employed an in silico approach to specifically target the HLP of Streptococcus mutans with available approved drugs from DrugBank. Computational analysis showed conserved regions in DNA-binding domain of the S. mutans HLP and its homologues in 47-49 and 78-79 residues. The S. mutans HLP was found to be closely related within streptococcal species in phylogenetic analysis. Alanine and lysine were found to be higher in the protein which is the characteristic of histone-like proteins. The crystal structure of S. mutans HLP is similar to HLP from Mycobacterium tuberculosis despite their sequential variations and evolutionary distance. Etravirine, Abacavir, Adenosine phosphate, Flucloxacillin, Nelarabine, and Regadenoson were found to efficiently bind at the DNA binding domain of S. mutans HLP. From these results it can be concluded that these drugs can be repurposed to control streptococcal infections.

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Crystal structure of histone-like protein fromStreptococcus mutansrefined to 1.9 Å resolution

Cited by 7 publications

References 53 publications

HU of Streptococcus pneumoniae Is Essential for the Preservation of DNA Supercoiling

HU of Streptococcus pneumoniae Is Essential for the Preservation of DNA Supercoiling

Disruption of the M949_RS01915 gene changed the bacterial lipopolysaccharide pattern, pathogenicity and gene expression of Riemerella anatipestifer

In Silico Drug Repurposing to Target Histone-Like Protein of Streptococcus Mutans

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