1. Inhibitor Targeting the Interface between Monomers of HU Protein from Spiroplasma melliferum Disrupts Conformational Dynamics and DNA-Binding Properties of the Protein
- Author
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D. E. Kamashev, E. V. Smirnova, D. A. Altukhov, Yu. K. Agapova, Tatiana V. Rakitina, and Vladimir I. Timofeev
- Subjects
010302 applied physics ,Virtual screening ,biology ,Chemistry ,HU Protein ,General Chemistry ,Bacterial genome size ,010403 inorganic & nuclear chemistry ,Condensed Matter Physics ,biology.organism_classification ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,Non-competitive inhibition ,Biochemistry ,0103 physical sciences ,Mollicutes ,Transcriptional regulation ,General Materials Science ,Electrophoretic mobility shift assay ,DNA - Abstract
Histone-like HU proteins are global regulators of the topology of the bacterial genome and are involved in transcriptional regulation. These proteins are essential for the survival of the simplest free-living microorganisms of the Mollicutes class and a number of pathogenic bacteria, including Mycobacterium tuberculosis and Streptococcus pneumonia, and are promising targets for the design of new antibiotics. However, the competitive inhibition of the DNA-binding ability of HU proteins is inefficient because of high flexibility and the large size of the DNA-binding site. Hence, an alternative approach was employed based on searching for molecules targeting the interface between two monomers. The three-dimensional structure of the HU protein from Spiroplasma melliferum (HUSpm) was used as a target for the virtual screening of the compound library and for the modeling of HUSpm in complex with the inhibitor. An analysis of the molecular dynamics trajectory calculated for the HUSpm–inhibitor complex confirmed the fact that the binding of the inhibitor at the interface between monomers leads to the disruption of conformational dynamics in the region of the DNA-binding domain. The gel retardation assay showed that the inhibitor actually disturbs DNA-binding activity of the protein, thereby indicating that this is a promising approach.
- Published
- 2020