Structure of pyrR (Rv1379) from Mycobacterium tuberculosis: a persistence gene and protein drug target

• Published in: Acta crystallographica. Section D, Biological crystallography. Biological crystallography., 2005-04, Vol.61 (4), p.355-364
• Main Authors: Kantardjieff, Katherine A., Vasquez, Carolina, Castro, Peter, Warfel, Nancy M., Rho, Beom-Seop, Lekin, Timothy, Kim, Chang-Yub, Segelke, Brent W., Terwilliger, Thomas C., Rupp, Bernhard
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antitubercular Agents - pharmacology; Bacterial Proteins - chemistry; Bacterial Proteins - drug effects; Bacterial Proteins - metabolism; Binding Sites; Crystallization; Crystallography, X-Ray; drug target structure; Genes, Bacterial; Genes, Regulator; Ligands; Models, Molecular; Molecular Sequence Data; Mycobacterium tuberculosis; Mycobacterium tuberculosis - enzymology; Mycobacterium tuberculosis - genetics; Pentosyltransferases - chemistry; Pentosyltransferases - drug effects; Pentosyltransferases - metabolism; Phosphoribosyl Pyrophosphate - metabolism; Protein Structure, Quaternary; pyrimidine biosynthesis; pyrR; Repressor Proteins - chemistry; Repressor Proteins - drug effects; Repressor Proteins - metabolism; RNA binding; Rv1379; Sequence Alignment; Uracil - metabolism; Uridine Monophosphate - metabolism
• ISSN: 1399-0047; 0907-4449; 1399-0047
• DOI: 10.1107/S090744490403389X

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 Å native structure of Mtb pyrR determined by the TB Structural Genomics Consortium facilities in trigonal space group P3121 is reported, with unit‐cell parameters a = 66.64, c = 154.72 Å 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.