6apv

Trypanosoma brucei hypoxanthine guanine phosphoribosyltransferase in complex with [(2-{[2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethyl][(E)-2-phosphonoethenyl]amino}ethoxy)methyl]phosphonic acid

spinqualitylabelsall models 6apv, resolution 1.99Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6apv is a 4 chain structure with sequence from Trypanosoma brucei brucei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.993Å Ligands: 3L4, MG, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HPRT_TRYBB Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway (By similarity). Publication Abstract from PubMed Due to toxicity and compliance issues and the emergence of resistance to current medications new drugs for the treatment of Human African Trypanosomiasis are needed. A potential approach to developing novel anti-trypanosomal drugs is by inhibition of the 6-oxopurine salvage pathways which synthesise the nucleoside monophosphates required for DNA/RNA production. This is in view of the fact that trypanosomes lack the machinery for de novo synthesis of the purine ring. To provide validation for this approach as a drug target, we have RNAi silenced the three 6-oxopurine phosphoribosyltransferase (PRTase) isoforms in the infectious stage of Trypanosoma brucei demonstrating that the combined activity of these enzymes is critical for the parasites' viability. Furthermore, we have determined crystal structures of two of these isoforms in complex with several acyclic nucleoside phosphonates (ANPs), a class of compound previously shown to inhibit 6-oxopurine PRTases from several species including Plasmodium falciparum. The most potent of these compounds have Ki values as low as 60 nM, and IC50 values in cell based assays as low as 4 muM. This data provides a solid platform for further investigations into the use of this pathway as a target for anti-trypanosomal drug discovery. Evaluation of the Trypanosoma brucei 6-oxopurine salvage pathway as a potential target for drug discovery.,Dolezelova E, Teran D, Gahura O, Kotrbova Z, Prochazkova M, Keough D, Spacek P, Hockova D, Guddat L, Zikova A PLoS Negl Trop Dis. 2018 Feb 26;12(2):e0006301. doi:, 10.1371/journal.pntd.0006301. eCollection 2018 Feb. PMID:29481567 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoribosyltransferase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA