期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2116278119
关键词
HU; bacteriophage; nucleoid; plasmodium; Gp46
资金
- National Key R&D Program of China [2021YFA1301200, 2021YFA1301201]
- National Natural Science Foundation of China [81871662]
- Key Research and Development Plan of Shaanxi Province [2021ZDLSF01-10, 2019ZDLSF03-02]
The HU protein is crucial for bacterial cell viability and serves as an antibiotic target. This study reveals that Gp46 from bacteriophage SPO1 can inhibit HU, leading to growth defects in bacteria. Through structural analysis, it is found that Gp46 occupies the DNA binding site of HU, thus preventing DNA binding. This discovery provides valuable insights into developing antibacterial and anti-malaria drugs.
The architectural protein histone-like protein from Escherichia coli strain U93 (HU) is the most abundant bacterial DNA binding protein and highly conserved among bacteria and Apicomplexan parasites. It not only binds to double-stranded DNA (dsDNA) to maintain DNA stability but also, interacts with RNAs to regulate transcription and translation. Importantly, HU is essential to cell viability for many bacteria; hence, it is an important antibiotic target. Here, we report that Gp46 from bacteriophage SPO1 of Bacillus subtilis is an HU inhibitor whose expression prevents nucleoid segregation and causes filamentous morphology and growth defects in bacteria. We determined the solution structure of Gp46 and revealed a striking negatively charged surface. An NMR-derived structural model for the Gp46-HU complex shows that Gp46 occupies the DNA binding motif of the HU and therefore, occludes DNA binding, revealing a distinct strategy for HU inhibition. We identified the key residues responsible for the interaction that are conserved among HUs of bacteria and Apicomplexans, including clinically significant Mycobacterium tuberculosis, Acinetobacter baumannii, and Plasmodium falciparum, and confirm that Gp46 can also interact with these HUs. Our findings provide detailed insight into a mode of HU inhibition that provides a useful foundation for the development of antibacteria and anti-malaria drugs.
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