6apt: Difference between revisions
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<StructureSection load='6apt' size='340' side='right'caption='[[6apt]], [[Resolution|resolution]] 1.79Å' scene=''> | <StructureSection load='6apt' size='340' side='right'caption='[[6apt]], [[Resolution|resolution]] 1.79Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6apt]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6APT OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6apt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei Trypanosoma brucei brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6APT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6APT FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=45T:{[(2S)-3-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)PROPANE-1,2-DIYL]BIS(OXYETHANE-2,1-DIYL)}BIS(PHOSPHONIC+ACID)'>45T</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.795Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=45T:{[(2S)-3-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)PROPANE-1,2-DIYL]BIS(OXYETHANE-2,1-DIYL)}BIS(PHOSPHONIC+ACID)'>45T</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6apt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6apt OCA], [https://pdbe.org/6apt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6apt RCSB], [https://www.ebi.ac.uk/pdbsum/6apt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6apt ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/HPRT_TRYBB 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). | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Trypanosoma brucei brucei]] | ||
[[Category: | [[Category: Guddat LW]] | ||
[[Category: | [[Category: Teran D]] | ||
Latest revision as of 17:22, 4 October 2023
Trypanosoma brucei hypoxanthine guanine phosphoribosyltransferase in complex with {[(2S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)propane-1,2-diyl]bis(oxyethane-2,1-diyl)}bis(phosphonic acid)Trypanosoma brucei hypoxanthine guanine phosphoribosyltransferase in complex with {[(2S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)propane-1,2-diyl]bis(oxyethane-2,1-diyl)}bis(phosphonic acid)
Structural highlights
FunctionHPRT_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 PubMedDue 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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