Structural basis of DNA sequence recognition by the response regulator PhoP in Mycobacterium tuberculosis

• Published in: Scientific reports 2016-04, Vol.6 (1), p.24442-24442, Article 24442
• Main Authors: He, Xiaoyuan, Wang, Liqin, Wang, Shuishu
• Format: Article
• Language: English
• Subjects: 631/45/535/1266; 631/45/612/1229; 82/83; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Crystal structure; Deoxyribonucleic acid; DNA; DNA structure; DNA, Bacterial - chemistry; DNA, Bacterial - metabolism; Drug development; Gene Expression Regulation, Bacterial; Humanities and Social Sciences; Models, Molecular; multidisciplinary; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - metabolism; Nucleic Acid Conformation; Nucleotide sequence; Phosphorylation; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization; Science; Science (multidisciplinary); Spacer; Structure-Activity Relationship; Transcription; Tuberculosis; Virulence factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep24442

The transcriptional regulator PhoP is an essential virulence factor in Mycobacterium tuberculosis , and it presents a target for the development of new anti-tuberculosis drugs and attenuated tuberculosis vaccine strains. PhoP binds to DNA as a highly cooperative dimer by recognizing direct repeats of 7-bp motifs with a 4-bp spacer. To elucidate the PhoP-DNA binding mechanism, we determined the crystal structure of the PhoP-DNA complex. The structure revealed a tandem PhoP dimer that bound to the direct repeat. The surprising tandem arrangement of the receiver domains allowed the four domains of the PhoP dimer to form a compact structure, accounting for the strict requirement of a 4-bp spacer and the highly cooperative binding of the dimer. The PhoP-DNA interactions exclusively involved the effector domain. The sequence-recognition helix made contact with the bases of the 7-bp motif in the major groove, and the wing interacted with the adjacent minor groove. The structure provides a starting point for the elucidation of the mechanism by which PhoP regulates the virulence of M. tuberculosis and guides the design of screening platforms for PhoP inhibitors.