4RHT: Crystal Structures Of Mycobacterium Tuberculosis 6-oxopurine Phosphoribosyltransferase Which Is A Potential Target For Drug Development Against This Disease

Human tuberculosis is a chronic infectious disease affecting millions of lives. Because of emerging resistance to current medications, new therapeutic drugs are needed. One potential new target is hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT), a key enzyme of the purine salvage pathway. Here, newly synthesized acyclic nucleoside phosphonates (ANPs) have been shown to be competitive inhibitors of MtHGPRT with Ki values as low as 0.69 muM. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 muM and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 muM). In addition, the first crystal structures of MtHGPRT (2.03-2.76 A resolution) have been determined, three of these in complex with novel ANPs and one with GMP and pyrophosphate. These data provide a solid foundation for the further development of ANPs as selective inhibitors of MtHGPRT and as antituberculosis agents.
PDB ID: 4RHTDownload
MMDB ID: 129441
PDB Deposition Date: 2014/10/3
Updated in MMDB: 2015/06
Experimental Method:
x-ray diffraction
Resolution: 2.76  Å
Source Organism:
Similar Structures:
Biological Unit for 4RHT: tetrameric; determined by author
Molecular Components in 4RHT
Label Count Molecule
Proteins (4 molecules)
Hypoxanthine-guanine Phosphoribosyltransferase HPT
Molecule annotation
Chemicals (16 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB