1cjb

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(New page: 200px<br /><applet load="1cjb" size="450" color="white" frame="true" align="right" spinBox="true" caption="1cjb, resolution 2.00&Aring;" /> '''MALARIAL PURINE PHOS...)
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[[Image:1cjb.gif|left|200px]]<br /><applet load="1cjb" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1cjb, resolution 2.00&Aring;" />
 
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'''MALARIAL PURINE PHOSPHORIBOSYLTRANSFERASE'''<br />
 
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==Overview==
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==MALARIAL PURINE PHOSPHORIBOSYLTRANSFERASE==
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Malaria is a leading cause of worldwide mortality from infectious disease., Plasmodium falciparum proliferation in human erythrocytes requires purine, salvage by hypoxanthine-guanine-xanthine phosphoribosyltransferase, (HGXPRTase). The enzyme is a target for the development of novel, antimalarials. Design and synthesis of transition-state analogue, inhibitors permitted cocrystallization with the malarial enzyme and, refinement of the complex to 2.0 A resolution. Catalytic site contacts in, the malarial enzyme are similar to those of human hypoxanthine-guanine, phosphoribosyltransferase (HGPRTase) despite distinct substrate, specificity. The crystal structure of malarial HGXPRTase with bound, inhibitor, pyrophosphate, and two Mg(2+) ions reveals features unique to, the transition-state analogue complex. Substrate-assisted catalysis occurs, by ribooxocarbenium stabilization from the O5' lone pair and a, pyrophosphate oxygen. A dissociative reaction coordinate path is, implicated in which the primary reaction coordinate motion is the ribosyl, C1' in motion between relatively immobile purine base and, (Mg)(2)-pyrophosphate. Several short hydrogen bonds form in the complex of, the enzyme and inhibitor. The proton NMR spectrum of the transition-state, analogue complex of malarial HGXPRTase contains two downfield signals at, 14.3 and 15.3 ppm. Despite the structural similarity to the human enzyme, the NMR spectra of the complexes reveal differences in hydrogen bonding, between the transition-state analogue complexes of the human and malarial, HG(X)PRTases. The X-ray crystal structures and NMR spectra reveal chemical, and structural features that suggest a strategy for the design of, malaria-specific transition-state inhibitors.
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<StructureSection load='1cjb' size='340' side='right'caption='[[1cjb]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1cjb]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. The July 2012 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)'' by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2012_7 10.2210/rcsb_pdb/mom_2012_7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CJB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1CJB FirstGlance]. <br>
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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&#8491;</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=IRP:(1S)-1(9-DEAZAHYPOXANTHIN-9YL)1,4-DIDEOXY-1,4-IMINO-D-RIBITOL-5-PHOSPHATE'>IRP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=POP:PYROPHOSPHATE+2-'>POP</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=1cjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1cjb OCA], [https://pdbe.org/1cjb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1cjb RCSB], [https://www.ebi.ac.uk/pdbsum/1cjb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1cjb ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/HGXR_PLAFG HGXR_PLAFG] Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Works with guanine, hypoxanthine and xanthine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cj/1cjb_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1cjb ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Malaria is a leading cause of worldwide mortality from infectious disease. Plasmodium falciparum proliferation in human erythrocytes requires purine salvage by hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase). The enzyme is a target for the development of novel antimalarials. Design and synthesis of transition-state analogue inhibitors permitted cocrystallization with the malarial enzyme and refinement of the complex to 2.0 A resolution. Catalytic site contacts in the malarial enzyme are similar to those of human hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) despite distinct substrate specificity. The crystal structure of malarial HGXPRTase with bound inhibitor, pyrophosphate, and two Mg(2+) ions reveals features unique to the transition-state analogue complex. Substrate-assisted catalysis occurs by ribooxocarbenium stabilization from the O5' lone pair and a pyrophosphate oxygen. A dissociative reaction coordinate path is implicated in which the primary reaction coordinate motion is the ribosyl C1' in motion between relatively immobile purine base and (Mg)(2)-pyrophosphate. Several short hydrogen bonds form in the complex of the enzyme and inhibitor. The proton NMR spectrum of the transition-state analogue complex of malarial HGXPRTase contains two downfield signals at 14.3 and 15.3 ppm. Despite the structural similarity to the human enzyme, the NMR spectra of the complexes reveal differences in hydrogen bonding between the transition-state analogue complexes of the human and malarial HG(X)PRTases. The X-ray crystal structures and NMR spectra reveal chemical and structural features that suggest a strategy for the design of malaria-specific transition-state inhibitors.
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==About this Structure==
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The 2.0 A structure of malarial purine phosphoribosyltransferase in complex with a transition-state analogue inhibitor.,Shi W, Li CM, Tyler PC, Furneaux RH, Cahill SM, Girvin ME, Grubmeyer C, Schramm VL, Almo SC Biochemistry. 1999 Aug 3;38(31):9872-80. PMID:10433693<ref>PMID:10433693</ref>
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1CJB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with MG, IRP and POP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Hypoxanthine_phosphoribosyltransferase Hypoxanthine phosphoribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.8 2.4.2.8] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1CJB OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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The 2.0 A structure of malarial purine phosphoribosyltransferase in complex with a transition-state analogue inhibitor., Shi W, Li CM, Tyler PC, Furneaux RH, Cahill SM, Girvin ME, Grubmeyer C, Schramm VL, Almo SC, Biochemistry. 1999 Aug 3;38(31):9872-80. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10433693 10433693]
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</div>
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[[Category: Hypoxanthine phosphoribosyltransferase]]
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<div class="pdbe-citations 1cjb" style="background-color:#fffaf0;"></div>
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[[Category: Plasmodium falciparum]]
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[[Category: Single protein]]
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[[Category: Almo, S.C.]]
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[[Category: Cahill, S.M.]]
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[[Category: Furneaux, R.H.]]
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[[Category: Girvin, M.E.]]
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[[Category: Grubmeyer, C.]]
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[[Category: Li, C.M.]]
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[[Category: Schramm, V.L.]]
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[[Category: Shi, W.]]
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[[Category: Tyler, P.C.]]
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[[Category: IRP]]
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[[Category: MG]]
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[[Category: POP]]
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[[Category: malaria]]
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[[Category: phosphoribosyltransferase]]
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[[Category: purine salvage]]
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[[Category: transition state inhibitor]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 12:30:37 2007''
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==See Also==
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*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Plasmodium falciparum]]
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[[Category: RCSB PDB Molecule of the Month]]
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[[Category: Almo SC]]
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[[Category: Cahill SM]]
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[[Category: Furneaux RH]]
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[[Category: Girvin ME]]
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[[Category: Grubmeyer C]]
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[[Category: Li CM]]
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[[Category: Schramm VL]]
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[[Category: Shi W]]
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[[Category: Tyler PC]]

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MALARIAL PURINE PHOSPHORIBOSYLTRANSFERASE

PDB ID 1cjb

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