4rhy

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==Crystal structures of Mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase which is a potential target for drug development against this disease==
==Crystal structures of Mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase which is a potential target for drug development against this disease==
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<StructureSection load='4rhy' size='340' side='right' caption='[[4rhy]], [[Resolution|resolution]] 2.32&Aring;' scene=''>
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<StructureSection load='4rhy' size='340' side='right'caption='[[4rhy]], [[Resolution|resolution]] 2.32&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4rhy]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RHY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RHY FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4rhy]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Ra Mycobacterium tuberculosis H37Ra]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RHY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RHY FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3QG:[2-({2-[BIS(2-PHOSPHONOETHYL)AMINO]ETHYL}[2-(6-OXO-3,6-DIHYDRO-9H-PURIN-9-YL)ETHYL]AMINO)ETHYL]PHOSPHONIC+ACID'>3QG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3196&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4rhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rhy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rhy RCSB], [http://www.ebi.ac.uk/pdbsum/4rhy PDBsum]</span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3QG:[2-({2-[BIS(2-PHOSPHONOETHYL)AMINO]ETHYL}[2-(6-OXO-3,6-DIHYDRO-9H-PURIN-9-YL)ETHYL]AMINO)ETHYL]PHOSPHONIC+ACID'>3QG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4rhy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rhy OCA], [https://pdbe.org/4rhy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rhy RCSB], [https://www.ebi.ac.uk/pdbsum/4rhy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rhy ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/HGPRT_MYCTU HGPRT_MYCTU] Purine salvage pathway enzyme that catalyzes the transfer of the ribosyl-5-phosphate group from 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) to the N9 position of the 6-oxopurines hypoxanthine and guanine to form the corresponding ribonucleotides IMP (inosine 5'-monophosphate) and GMP (guanosine 5'-monophosphate), with the release of PPi (PubMed:19362594, PubMed:25915781). Thus, specifically recycles hypoxanthine and guanine imported from the external medium, and converts them to IMP and GMP, respectively. Cannot use xanthine as substrate (PubMed:19362594).<ref>PMID:19362594</ref> <ref>PMID:25915781</ref>
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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 &gt;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.
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First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity.,Eng WS, Hockova D, Spacek P, Janeba Z, West NP, Woods K, Naesens LM, Keough DT, Guddat LW J Med Chem. 2015 May 13. PMID:25915781<ref>PMID:25915781</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
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</div>
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*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Eng, W S]]
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[[Category: Large Structures]]
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[[Category: Guddat, L W]]
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[[Category: Mycobacterium tuberculosis H37Ra]]
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[[Category: Hockova, D]]
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[[Category: Eng WS]]
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[[Category: Keough, D T]]
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[[Category: Guddat LW]]
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[[Category: Naesens, L M.J]]
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[[Category: Hockova D]]
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[[Category: Spacek, P]]
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[[Category: Keough DT]]
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[[Category: West, N P]]
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[[Category: Naesens LMJ]]
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[[Category: Woods, K]]
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[[Category: Spacek P]]
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[[Category: 6-oxopurine phosphoribosyltransferase]]
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[[Category: West NP]]
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[[Category: Cytoplasmic]]
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[[Category: Woods K]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Crystal structures of Mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase which is a potential target for drug development against this disease

PDB ID 4rhy

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