Structure of pyrR (Rv1379) from Mycobacterium tuberculosis: a persistence gene and protein drug target.
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.
Kantardjieff
Katherine A
KA
Department of Chemistry and Biochemistry and W. M. Keck Foundation Center for Molecular Structure, California State University Fullerton, Fullerton, CA 92834, USA.
Vasquez
Carolina
C
Castro
Peter
P
Warfel
Nancy M
NM
Rho
Beom Seop
BS
Lekin
Timothy
T
Kim
Chang Yub
CY
Segelke
Brent W
BW
Terwilliger
Thomas C
TC
Rupp
Bernhard
B
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
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