title: Structural basis of DNA sequence recognition by the response regulator PhoP in Mycobacterium tuberculosis.
abstract: 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.
authors.affiliation: Department of Biochemistry &Molecular Biology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Biochemistry &Molecular Biology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814, USA.
authors.forename: Liqin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry &Molecular Biology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814, USA.
authors.forename: Shuishu
authors.initials: S
authors.lastname: Wang
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D004269:DNA, Bacterial / Q000737:chemistry* / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; C061064:PhoP protein, Bacteria