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4rhu

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Revision as of 06:57, 2 March 2023

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

Structural highlights

4rhu is a 6 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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).^[1] ^[2]

Publication Abstract from PubMed

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 >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.

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Biazus G, Schneider CZ, Palma MS, Basso LA, Santos DS. Hypoxanthine-guanine phosphoribosyltransferase from Mycobacterium tuberculosis H37Rv: cloning, expression, and biochemical characterization. Protein Expr Purif. 2009 Aug;66(2):185-90. PMID:19362594 doi:10.1016/j.pep.2009.04.001
↑ Eng WS, Hockova D, Spacek P, Janeba Z, West NP, Woods K, Naesens LM, Keough DT, Guddat LW. First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity. J Med Chem. 2015 May 13. PMID:25915781 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00611
↑ Eng WS, Hockova D, Spacek P, Janeba Z, West NP, Woods K, Naesens LM, Keough DT, Guddat LW. First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity. J Med Chem. 2015 May 13. PMID:25915781 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00611

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4rhu"

@@ Line 3: / Line 3: @@
 <StructureSection load='4rhu' size='340' side='right'caption='[[4rhu]], [[Resolution|resolution]] 2.57&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4rhu]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RHU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RHU FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4rhu]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RHU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RHU FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3QE:{[(2R)-3-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)PROPANE-1,2-DIYL]BIS(OXYETHANE-2,1-DIYL)}BIS(PHOSPHONIC+ACID)'>3QE</scene>, <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=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3QE:{[(2R)-3-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)PROPANE-1,2-DIYL]BIS(OXYETHANE-2,1-DIYL)}BIS(PHOSPHONIC+ACID)'>3QE</scene>, <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=MG:MAGNESIUM+ION'>MG</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">P425_03767, RVBD_3624c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</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=4rhu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rhu OCA], [https://pdbe.org/4rhu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rhu RCSB], [https://www.ebi.ac.uk/pdbsum/4rhu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rhu ProSAT]</span></td></tr>
-<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=4rhu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rhu OCA], [http://pdbe.org/4rhu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rhu RCSB], [http://www.ebi.ac.uk/pdbsum/4rhu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rhu ProSAT]</span></td></tr>
 </table>
+== Function ==
+[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 17: / Line 18: @@
 </div>
 <div class="pdbe-citations 4rhu" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
 == References ==
 <references/>
@@ Line 22: / Line 26: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Myctu]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Eng, W S]]
+[[Category: Eng WS]]
-[[Category: Guddat, L W]]
+[[Category: Guddat LW]]
-[[Category: Hockova, D]]
+[[Category: Hockova D]]
-[[Category: Keough, D T]]
+[[Category: Keough DT]]
-[[Category: Naesens, L M.J]]
+[[Category: Naesens LMJ]]
-[[Category: Spacek, P]]
+[[Category: Spacek P]]
-[[Category: West, N P]]
+[[Category: West NP]]
-[[Category: Woods, K]]
+[[Category: Woods K]]
-[[Category: 6-oxopurine phosphoribosyltransferase]]
-[[Category: Acyclic nucleoside phosphonate inhibitor]]
-[[Category: Hypoxanthine-guanine phosphoribosyltransferase]]
-[[Category: Purine salvage pathway]]
-[[Category: Transferase-transferase inhibitor complex]]

4rhu

From Proteopedia

Revision as of 06:57, 2 March 2023

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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