title: Structure of pyrR (Rv1379) from Mycobacterium tuberculosis: a persistence gene and protein drug target.
abstract: The Mycobacterium tuberculosis pyrR gene (Rv1379) encodes a protein that regulates the expression of pyrimidine-nucleotide biosynthesis (pyr) genes in a UMP-dependent manner. Because pyrimidine biosynthesis is an essential step in the progression of TB, the gene product pyrR is an attractive antitubercular drug target. The 1.9 A native structure of Mtb pyrR determined by the TB Structural Genomics Consortium facilities in trigonal space group P3(1)21 is reported, with unit-cell parameters a = 66.64, c = 154.72 A at 120 K and two molecules in the asymmetric unit. The three-dimensional structure and residual uracil phosphoribosyltransferase activity point to a common PRTase ancestor for pyrR. However, while PRPP- and UMP-binding sites have been retained in Mtb pyrR, a distinct dimer interaction among subunits creates a deep positively charged cleft capable of binding pyr mRNA. In silico screening of pyrimidine-nucleoside analogs has revealed a number of potential lead compounds that, if bound to Mtb pyrR, could facilitate transcriptional attenuation, particularly cyclopentenyl nucleosides.
authors.affiliation: Department of Chemistry and Biochemistry and W. M. Keck Foundation Center for Molecular Structure, California State University Fullerton, Fullerton, CA 92834, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Kantardjieff
authors.forename: Carolina
authors.initials: C
authors.lastname: Vasquez
authors.forename: Peter
authors.initials: P
authors.lastname: Castro
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Warfel
authors.forename: Beom Seop
authors.initials: BS
authors.lastname: Rho
authors.forename: Timothy
authors.initials: T
authors.lastname: Lekin
authors.forename: Chang Yub
authors.initials: CY
authors.lastname: Kim
authors.forename: Brent W
authors.initials: BW
authors.lastname: Segelke
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Terwilliger
authors.forename: Bernhard
authors.initials: B
authors.lastname: Rupp
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D005798:Genes, Bacterial; D005809:Genes, Regulator; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology / Q000235:genetics*; D010430:Pentosyltransferases / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D020836:Protein Structure, Quaternary; D012097:Repressor Proteins / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D016415:Sequence Alignment; D014498:Uracil / Q000378:metabolism; D014542:Uridine Monophosphate / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D008024:Ligands; D012097:Repressor Proteins; D014498:Uracil; D010754:Phosphoribosyl Pyrophosphate; D014542:Uridine Monophosphate; D010430:Pentosyltransferases; C098851:PyrR protein, bacteria; C023269:uracil phosphoribosyltransferase