5k51: Difference between revisions
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==Trypanosome brucei Hypoxanthine-guanine phosphoribosyltranferase in complex with a 9-[5-(phosphonoheptyl]hypoxanthine== | |||
<StructureSection load='5k51' size='340' side='right'caption='[[5k51]], [[Resolution|resolution]] 2.96Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5k51]] is a 4 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=5K51 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5K51 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]] 2.956Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6QD:5-(6-OXIDANYLIDENE-3~{H}-PURIN-9-YL)PENTYLPHOSPHONIC+ACID'>6QD</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=5k51 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k51 OCA], [https://pdbe.org/5k51 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5k51 RCSB], [https://www.ebi.ac.uk/pdbsum/5k51 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5k51 ProSAT]</span></td></tr> | |||
</table> | |||
== 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;"> | |||
== Publication Abstract from PubMed == | |||
Human African Trypanosomiasis (HAT) is a life-threatening infectious disease caused by the protozoan parasite, Trypanosoma brucei (Tbr). Due to the debilitating side effects of the current therapeutics and the emergence of resistance to these drugs, new medications for this disease need to be developed. One potential new drug target is 6-oxopurine phosphoribosyltransferase (PRT), an enzyme central to the purine salvage pathway and whose activity is critical for the production of the nucleotides (GMP and IMP) required for DNA/RNA synthesis within this protozoan parasite. Here, the first crystal structures of this enzyme have been determined, these in complex with GMP and IMP and with three acyclic nucleoside phosphonate (ANP) inhibitors. The Ki values for GMP and IMP are 30.5 muM and 77 muM, respectively. Two of the ANPs have Ki values considerably lower than for the nucleotides, 2.3 muM (with guanine as base) and 15.8 muM (with hypoxanthine as base). The crystal structures show that when two of the ANPs bind, they induce an unusual conformation change to the loop where the reaction product, pyrophosphate, is expected to bind. This and other structural differences between the Tbr and human enzymes suggest selective inhibitors for the Tbr enzyme can be designed. | |||
Crystal structures and inhibition of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase.,Teran D, Hockova D, Cesnek M, Zikova A, Naesens L, Keough DT, Guddat LW Sci Rep. 2016 Oct 27;6:35894. doi: 10.1038/srep35894. PMID:27786284<ref>PMID:27786284</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Guddat | <div class="pdbe-citations 5k51" 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]] | |||
[[Category: Guddat L]] | |||
[[Category: Teran D]] | |||
Latest revision as of 12:51, 27 September 2023
Trypanosome brucei Hypoxanthine-guanine phosphoribosyltranferase in complex with a 9-[5-(phosphonoheptyl]hypoxanthineTrypanosome brucei Hypoxanthine-guanine phosphoribosyltranferase in complex with a 9-[5-(phosphonoheptyl]hypoxanthine
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 PubMedHuman African Trypanosomiasis (HAT) is a life-threatening infectious disease caused by the protozoan parasite, Trypanosoma brucei (Tbr). Due to the debilitating side effects of the current therapeutics and the emergence of resistance to these drugs, new medications for this disease need to be developed. One potential new drug target is 6-oxopurine phosphoribosyltransferase (PRT), an enzyme central to the purine salvage pathway and whose activity is critical for the production of the nucleotides (GMP and IMP) required for DNA/RNA synthesis within this protozoan parasite. Here, the first crystal structures of this enzyme have been determined, these in complex with GMP and IMP and with three acyclic nucleoside phosphonate (ANP) inhibitors. The Ki values for GMP and IMP are 30.5 muM and 77 muM, respectively. Two of the ANPs have Ki values considerably lower than for the nucleotides, 2.3 muM (with guanine as base) and 15.8 muM (with hypoxanthine as base). The crystal structures show that when two of the ANPs bind, they induce an unusual conformation change to the loop where the reaction product, pyrophosphate, is expected to bind. This and other structural differences between the Tbr and human enzymes suggest selective inhibitors for the Tbr enzyme can be designed. Crystal structures and inhibition of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase.,Teran D, Hockova D, Cesnek M, Zikova A, Naesens L, Keough DT, Guddat LW Sci Rep. 2016 Oct 27;6:35894. doi: 10.1038/srep35894. PMID:27786284[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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