6aqo: Difference between revisions
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==Crystal structure of hypoxanthine-guanine-xanthine phosphorybosyltranferase 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)== | |||
<StructureSection load='6aqo' size='340' side='right'caption='[[6aqo]], [[Resolution|resolution]] 2.64Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6aqo]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei_TREU927 Trypanosoma brucei brucei TREU927]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AQO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AQO FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.64Å</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=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6aqo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6aqo OCA], [https://pdbe.org/6aqo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6aqo RCSB], [https://www.ebi.ac.uk/pdbsum/6aqo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6aqo ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q38CA1_TRYB2 Q38CA1_TRYB2] | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:29481567</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Gudday | <div class="pdbe-citations 6aqo" style="background-color:#fffaf0;"></div> | ||
[[Category: Teran | |||
==See Also== | |||
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Trypanosoma brucei brucei TREU927]] | |||
[[Category: Gudday LW]] | |||
[[Category: Teran D]] | |||
Latest revision as of 17:23, 4 October 2023
Crystal structure of hypoxanthine-guanine-xanthine phosphorybosyltranferase 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)Crystal structure of hypoxanthine-guanine-xanthine phosphorybosyltranferase 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
FunctionPublication 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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