Structural basis of the high thermal stability of the histone-like HU protein from the mollicute Spiroplasma melliferum KC3

Boyko, K.М.; Rakitina, Tatiana V.; Korzhenevskiy, D.A.; Vlaskina, Anna V.; Agapova, Yuliya K.; Kamashev, Dmitri; Kleymenov, Sergey Y.; Popov, Vladimir O.

doi:10.1038/srep36366

Cited by 26 publications

(15 citation statements)

References 43 publications

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“…S . melliferum HU has increased number of phenylalanine residues, which enhances hydrophobic interactions in its dimeric interface [ 38 ], and a two-residues insertion within the loop between alpha helixes 1 and 2 ( Fig 8 ). M .…”

Section: Resultsmentioning

confidence: 99%

“…volcanium and T. thermophiles [ 37 ]; another nature of thermostability was demonstrated for S . melliferum HU [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

“…gallisepticum HU has multiple amino acid substitutions in the most conservative regions [ 8 , 41 ], while S . melliferum HU has increased number of phenylalanine residues and enhanced hydrophobic interactions in its dimeric interface [ 38 ]. We found that in respect to dsDNA binding, only S .…”

Section: Introductionmentioning

confidence: 99%

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Comparison of histone-like HU protein DNA-binding properties and HU/IHF protein sequence alignment

et al. 2017

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BackgroundThe structure and function of bacterial nucleoid are controlled by histone-like proteins of HU/IHF family, omnipresent in bacteria and also founding archaea and some eukaryotes.HU protein binds dsDNA without sequence specificity and avidly binds DNA structures with propensity to be inclined such as forks, three/four-way junctions, nicks, overhangs and DNA bulges. Sequence comparison of thousands of known histone-like proteins from diverse bacteria phyla reveals relation between HU/IHF sequence, DNA–binding properties and other protein features.Methodology and principal findingsPerformed alignment and clusterization of the protein sequences show that HU/IHF family proteins can be unambiguously divided into three groups, HU proteins, IHF_A and IHF_B proteins. HU proteins, IHF_A and IHF_B proteins are further partitioned into several clades for IHF and HU; such a subdivision is in good agreement with bacterial taxonomy. We also analyzed a hundred of 3D fold comparative models built for HU sequences from all revealed HU clades. It appears that HU fold remains similar in spite of the HU sequence variations. We studied DNA–binding properties of HU from N. gonorrhoeae, which sequence is similar to one of E.coli HU, and HU from M. gallisepticum and S. melliferum which sequences are distant from E.coli protein. We found that in respect to dsDNA binding, only S. melliferum HU essentially differs from E.coli HU. In respect to binding of distorted DNA structures, S. melliferum HU and E.coli HU have similar properties but essentially different from M. gallisepticum HU and N. gonorrhea HU. We found that in respect to dsDNA binding, only S. melliferum HU binds DNA in non-cooperative manner and both mycoplasma HU bend dsDNA stronger than E.coli and N. gonorrhoeae. In respect to binding to distorted DNA structures, each HU protein has its individual profile of affinities to various DNA-structures with the increased specificity to DNA junction.Conclusions and significanceHU/IHF family proteins sequence alignment and classification are updated. Comparative modeling demonstrates that HU protein 3D folding’s even more conservative than HU sequence. For the first time, DNA binding characteristics of HU from N. gonorrhoeae, M. gallisepticum and S. melliferum are studied. Here we provide detailed analysis of the similarity and variability of DNA-recognizing and bending of four HU proteins from closely and distantly related HU clades.

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Section: Resultsmentioning

confidence: 99%

“…volcanium and T. thermophiles [ 37 ]; another nature of thermostability was demonstrated for S . melliferum HU [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

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Comparison of histone-like HU protein DNA-binding properties and HU/IHF protein sequence alignment

et al. 2017

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“…The inhibitory molecules can be designed in a timely and cost‐effective manner using rationale structure‐based drug‐discovery approach, which requires structural information of target protein. Recent past witnessed several structural and functional studies on proteins of histone‐like DNA binding proteins (HU) family owing to their potential therapeutic relevance in the development of novel antibiotics, however, so far, no such investigations have been carried out on HU proteins of H. pylori strains, which are equally important not only to guide the rational drug discovery process, but also will help to infer conformational rationale for its remarkable functional heterogeneity. Within this research framework, we started the characterization of structural and motional features of Hup using nuclear magnetic resonance (NMR)‐based methods.…”

Section: Introductionmentioning

confidence: 99%

NMR elucidation of monomer–dimer transition and conformational heterogeneity in histone‐like DNA binding protein of Helicobacter pylori

Jaiswal

Raikwal

Pandey

et al. 2018

Magnetic Reson in Chemistry

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Helicobacter pylori (H. pylori) colonizes under harsh acidic/oxidative stress conditions of human gastrointestinal tract and can survive there for infinitely longer durations of host life. The bacterium expresses several harbinger proteins to facilitate its persistent colonization under such conditions. One such protein in H. pylori is histone-like DNA binding protein (Hup), which in its homo-dimeric form binds to DNA to perform various DNA dependent cellular activities. Further, it also plays an important role in protecting the genomic DNA from oxidative stress and acidic denaturation. Legitimately, if the binding of Hup to DNA is suppressed, it will directly impact on the survival of the bacterium, thus making Hup a potential therapeutic target for developing new anti-H. pylori agents. However, to inhibit the binding of Hup to DNA, it is necessary to gain detailed insights into the molecular and structural basis of Hup-dimerization and its binding mechanism to DNA. As a first step in this direction, we report here the nuclear magnetic resonance (NMR) assignments and structural features of Hup at pH 6.0. The study revealed the occurrence of dynamic equilibrium between its monomer and dimer conformations. The dynamic equilibrium was found to shifting towards dimer both at low temperature and low pH; whereas DNA binding studies evidenced that the protein binds to DNA in its dimeric form. These preliminary investigations correlate very well with the diverse functionality of protein and will form the basis for future studies aiming to develop novel anti-H. pylori agents employing structure-based-rational drug discovery approach.

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“…We followed the design strategy proposed in 35 for the development of chemical inhibitors of HU protein from mycoplasma Spiroplasma melliferum (HUSpm). High-resolution spatial structure of HUSpm (PDB ID 5L8Z 9 ) was used for virtual screening and docking, while its structure in solution (PDB ID 5OGU 37 ) was employed for the comparative analysis of conformational dynamics observed in the HUSpm dimer upon either independent or sequential addition of short double-stranded DNA and an inhibitor. We found out that bisphenol derivatives of fluorene (BDFs) inhibit DNA binding properties of three model HU proteins (HUSpm, HUα-homodimer from E. coli (HUEc) and HU from another mycoplasma species Mycoplasma gallisepticum (HUMgal)).…”

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confidence: 99%

Structure-based inhibitors targeting the alpha-helical domain of the Spiroplasma melliferum histone-like HU protein

Agapova

Altukhov

Тимофеев

et al. 2020

Sci Rep

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Here we report bisphenol derivatives of fluorene (BDFs) as a new type of chemical probes targeting a histone-like HU protein, a global regulator of bacterial nucleoids, via its dimerization interface perturbation. BDFs were identified by virtual screening and molecular docking that targeted the core of DNA-binding β-saddle-like domain of the HU protein from Spiroplasma melliferum. However, NMR spectroscopy, complemented with molecular dynamics and site-directed mutagenesis, indicated that the actual site of the inhibitors’ intervention consists of residues from the α-helical domain of one monomer and the side portion of the DNA-binding domain of another monomer. BDFs inhibited DNA-binding properties of HU proteins from mycoplasmas S. melliferum, Mycoplasma gallicepticum and Escherichia coli with half-maximum inhibitory concentrations in the range between 5 and 10 µM. In addition, BDFs demonstrated antimicrobial activity against mycoplasma species, but not against E. coli, which is consistent with the compensatory role of other nucleoid-associated proteins in the higher bacteria. Further evaluation of antimicrobial effects of BDFs against various bacteria and viruses will reveal their pharmacological potential, and the allosteric inhibition mode reported here, which avoids direct competition for the binding site with DNA, should be considered in the development of small molecule inhibitors of nucleoid-associated proteins as well as other types of DNA-binding multimeric proteins.

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Structural basis of the high thermal stability of the histone-like HU protein from the mollicute Spiroplasma melliferum KC3

Cited by 26 publications

References 43 publications

Comparison of histone-like HU protein DNA-binding properties and HU/IHF protein sequence alignment

Comparison of histone-like HU protein DNA-binding properties and HU/IHF protein sequence alignment

NMR elucidation of monomer–dimer transition and conformational heterogeneity in histone‐like DNA binding protein of Helicobacter pylori

Structure-based inhibitors targeting the alpha-helical domain of the Spiroplasma melliferum histone-like HU protein

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