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

Area of Science:

• Structural Biology
• Molecular Biology
• Drug Discovery

Background:

• The Mycobacterium tuberculosis pyrR gene (Rv1379) encodes a protein crucial for regulating pyrimidine-nucleotide biosynthesis (pyr) genes.
• Pyrimidine biosynthesis is essential for tuberculosis (TB) progression, making the pyrR gene product a significant drug target.

Purpose of the Study:

• To determine the native structure of Mtb pyrR.
• To investigate the structural basis for pyrR's function and identify potential drug lead compounds.

Main Methods:

• X-ray crystallography was used to determine the 1.9 Å native structure of Mtb pyrR.
• In silico screening of pyrimidine-nucleoside analogs was performed.

Main Results:

• The Mtb pyrR structure was determined in the trigonal space group P3(1)21.
• The structure indicates a common phosphoribosyltransferase (PRTase) ancestor, retaining UMP- and PRPP-binding sites.
• A unique dimer interaction forms a cleft for pyr mRNA binding, and in silico screening identified potential transcriptional attenuation facilitators, including cyclopentenyl nucleosides.

Conclusions:

• The Mtb pyrR structure provides insights into its regulatory mechanism and common ancestry.
• Identified pyrimidine-nucleoside analogs show promise as lead compounds for antitubercular drug development targeting transcriptional attenuation.