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标题：Bacteriophage protein Gp46 is a cross-species inhibitor of nucleoid-associated HU proteins
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作者：Peipei Zhang ; Xiaohui Zhao ; Yawen Wang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：9
DOI：10.1073/pnas.2116278119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Histone-like protein from Escherichia coli strain U93 (HU) protein is the most abundant nucleoid-associated protein in bacteria, which plays a fundamental role in chromosomal compaction and organization. It is essential for most bacteria as well as Apicomplexans, thus an important target for the development of antimicrobial and antimalaria drugs. We report Gp46 as a phage protein HU inhibitor. It inhibits HU of Bacillus subtilis by occupying its DNA binding site, thus preventing chromosome segregation during cell division. As key residues for the interaction are highly conserved, Gp46 interacts with HUs of a broad range of pathogens, including many pathogenic bacteria and Apicomplexan parasites like Plasmodium falciparum. Thus, this cross-species property could benefit antibiotic and antimalaria drug development that targets HU. 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 antimalaria drugs.
关键词：enHUbacteriophagenucleoidplasmodiumGp46