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Title: Structure of the DNA-Binding Domain of the Response Regulator PhoP from Mycobacterium tuberculosis

Abstract

The PhoP-PhoR two-component signaling system from Mycobacterium tuberculosis is essential for the virulence of the tubercle bacillus. The response regulator, PhoP, regulates expression of over 110 genes. In order to elucidate the regulatory mechanism of PhoP, we determined the crystal structure of its DNA-binding domain (PhoPC). PhoPC exhibits a typical fold of the winged helix-turn-helix subfamily of response regulators. The structure starts with a four-stranded antiparallel {beta}-sheet, followed by a three-helical bundle of a-helices, and then a C-terminal {beta}-hairpin, which together with a short {beta}-strand between the first and second helices forms a three-stranded antiparallel {beta}-sheet. Structural elements are packed through a hydrophobic core, with the first helix providing a scaffold for the rest of the domain to pack. The second and third helices and the long, flexible loop between them form the helix-turn-helix motif, with the third helix being the recognition helix. The C-terminal {beta}-hairpin turn forms the wing motif. The molecular surfaces around the recognition helix and the wing residues show strong positive electrostatic potential, consistent with their roles in DNA binding and nucleotide sequence recognition. The crystal packing of PhoPC gives a hexamer ring, with neighboring molecules interacting in a head-to-tail fashion. This packing interface suggests thatmore » PhoPC could bind DNA in a tandem association. However, this mode of DNA binding is likely to be nonspecific because the recognition helix is partially blocked and would be prevented from inserting into the major groove of DNA. Detailed structural analysis and implications with respect to DNA binding are discussed.« less

Authors:
; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959807
Report Number(s):
BNL-82793-2009-JA
Journal ID: ISSN 0006-2960; BICHAW; TRN: US201016%%951
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemistry; Journal Volume: 46
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; BACILLUS; CRYSTAL STRUCTURE; DNA; ELECTROSTATICS; GENES; MYCOBACTERIUM TUBERCULOSIS; NUCLEOTIDES; RESIDUES; VIRULENCE; national synchrotron light source

Citation Formats

Wang,S., Engohang-Ndong, J., and Smith, I. Structure of the DNA-Binding Domain of the Response Regulator PhoP from Mycobacterium tuberculosis. United States: N. p., 2007. Web. doi:10.1021/bi700970a.
Wang,S., Engohang-Ndong, J., & Smith, I. Structure of the DNA-Binding Domain of the Response Regulator PhoP from Mycobacterium tuberculosis. United States. doi:10.1021/bi700970a.
Wang,S., Engohang-Ndong, J., and Smith, I. Mon . "Structure of the DNA-Binding Domain of the Response Regulator PhoP from Mycobacterium tuberculosis". United States. doi:10.1021/bi700970a.
@article{osti_959807,
title = {Structure of the DNA-Binding Domain of the Response Regulator PhoP from Mycobacterium tuberculosis},
author = {Wang,S. and Engohang-Ndong, J. and Smith, I.},
abstractNote = {The PhoP-PhoR two-component signaling system from Mycobacterium tuberculosis is essential for the virulence of the tubercle bacillus. The response regulator, PhoP, regulates expression of over 110 genes. In order to elucidate the regulatory mechanism of PhoP, we determined the crystal structure of its DNA-binding domain (PhoPC). PhoPC exhibits a typical fold of the winged helix-turn-helix subfamily of response regulators. The structure starts with a four-stranded antiparallel {beta}-sheet, followed by a three-helical bundle of a-helices, and then a C-terminal {beta}-hairpin, which together with a short {beta}-strand between the first and second helices forms a three-stranded antiparallel {beta}-sheet. Structural elements are packed through a hydrophobic core, with the first helix providing a scaffold for the rest of the domain to pack. The second and third helices and the long, flexible loop between them form the helix-turn-helix motif, with the third helix being the recognition helix. The C-terminal {beta}-hairpin turn forms the wing motif. The molecular surfaces around the recognition helix and the wing residues show strong positive electrostatic potential, consistent with their roles in DNA binding and nucleotide sequence recognition. The crystal packing of PhoPC gives a hexamer ring, with neighboring molecules interacting in a head-to-tail fashion. This packing interface suggests that PhoPC could bind DNA in a tandem association. However, this mode of DNA binding is likely to be nonspecific because the recognition helix is partially blocked and would be prevented from inserting into the major groove of DNA. Detailed structural analysis and implications with respect to DNA binding are discussed.},
doi = {10.1021/bi700970a},
journal = {Biochemistry},
number = ,
volume = 46,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}