Structure of pyrR (Rv1379) from Mycobacterium tuberculosis: A persistence gene and protein drug target
Journal Article
·
· Acta Crystallographica D
OSTI ID:15015178
The 1.9 {angstrom} native structure of pyrimidine biosynthesis regulatory protein encoded by the Mycobacterium tuberculosis pyrR gene (Rv1379) is reported. Because pyrimidine biosynthesis is an essential step in the progression of TB, pyrR is an attractive antitubercular drug target. The Mycobacterium tuberculosis pyrR gene (Rv1379) encodes a protein that regulates 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. We report the 1.9 {angstrom} native structure of Mtb pyrR determined by the TB Structural Genomics Consortium facilities (PDB entry 1W30) in trigonal space group P3{sub 1}21, with cell dimensions at 120K of a = 66.64 {angstrom}, c = 154.72 {angstrom}, and two molecules in the asymmetric unit. The 3D 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 novel 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 leads compounds that, if bound to Mtb pyrR, could facilitate transcriptional attenuation, particularly cyclopentenyl nucleosides.
- Research Organization:
- Lawrence Livermore National Lab., Livermore, CA (US)
- Sponsoring Organization:
- US Department of Energy (US)
- DOE Contract Number:
- W-7405-ENG-48
- OSTI ID:
- 15015178
- Report Number(s):
- UCRL-JRNL-207072
- Journal Information:
- Acta Crystallographica D, Journal Name: Acta Crystallographica D Journal Issue: 4 Vol. 61
- Country of Publication:
- United States
- Language:
- English
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