2j4e: Difference between revisions
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== | ==THE ITP COMPLEX OF HUMAN INOSINE TRIPHOSPHATASE== | ||
Inosine triphosphatase (ITPA) is a ubiquitous key regulator of cellular | <StructureSection load='2j4e' size='340' side='right'caption='[[2j4e]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2j4e]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2J4E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2J4E 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]] 2.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene>, <scene name='pdbligand=ITT:INOSINE+5-TRIPHOSPHATE'>ITT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=POP:PYROPHOSPHATE+2-'>POP</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=2j4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j4e OCA], [https://pdbe.org/2j4e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2j4e RCSB], [https://www.ebi.ac.uk/pdbsum/2j4e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2j4e ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/ITPA_HUMAN ITPA_HUMAN] Defects in ITPA are the cause of inosine triphosphate pyrophosphohydrolase deficiency (ITPAD) [MIM:[https://omim.org/entry/613850 613850]. It is a common inherited trait characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes and also leukocytes and fibroblasts. The pathological consequences of ITPA deficiency, if any, are unknown. However, it might have pharmacogenomic implications and be related to increased drug toxicity of purine analog drugs. Note=Three different human populations have been reported with respect to their ITPase activity: high, mean (25% of high) and low activity. The variant Thr-32 is associated with complete loss of enzyme activity, may be by altering the local secondary structure of the protein. Heterozygotes for this polymorphism have 22.5% of the control activity: this is consistent with a dimeric structure of the enzyme.[:]<ref>PMID:12384777</ref> <ref>PMID:12436200</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ITPA_HUMAN ITPA_HUMAN] Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triposphate (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy- and ribose forms. Probably excludes non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions.<ref>PMID:17090528</ref> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/j4/2j4e_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</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=2j4e ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inosine triphosphatase (ITPA) is a ubiquitous key regulator of cellular non-canonical nucleotide levels. It breaks down inosine and xanthine nucleotides generated by deamination of purine bases. Its enzymatic action prevents accumulation of ITP and reduces the risk of incorporation of potentially mutagenic inosine nucleotides into nucleic acids. Here we describe the crystal structure of human ITPA in complex with its prime substrate ITP, as well as the apoenzyme at 2.8 and 1.1A, respectively. These structures show for the first time the site of substrate and Mg2+ coordination as well as the conformational changes accompanying substrate binding in this class of enzymes. Enzyme substrate interactions induce an extensive closure of the nucleotide binding grove, resulting in tight interactions with the base that explain the high substrate specificity of ITPA for inosine and xanthine over the canonical nucleotides. One of the dimer contact sites is made up by a loop that is involved in coordinating the metal ion in the active site. We predict that the ITPA deficiency mutation P32T leads to a shift of this loop that results in a disturbed affinity for nucleotides and/or a reduced catalytic activity in both monomers of the physiological dimer. | |||
Crystal structure of human inosine triphosphatase. Substrate binding and implication of the inosine triphosphatase deficiency mutation P32T.,Stenmark P, Kursula P, Flodin S, Graslund S, Landry R, Nordlund P, Schuler H J Biol Chem. 2007 Feb 2;282(5):3182-7. Epub 2006 Nov 29. PMID:17138556<ref>PMID:17138556</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2j4e" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Arrowsmith C]] | |||
[[Category: Arrowsmith | [[Category: Berglund H]] | ||
[[Category: Busam R]] | |||
[[Category: Berglund | [[Category: Collins R]] | ||
[[Category: Busam | [[Category: Edwards A]] | ||
[[Category: Collins | [[Category: Ehn M]] | ||
[[Category: Edwards | [[Category: Flodin S]] | ||
[[Category: Ehn | [[Category: Flores A]] | ||
[[Category: Flodin | [[Category: Graslund S]] | ||
[[Category: Flores | [[Category: Hallberg BM]] | ||
[[Category: Graslund | [[Category: Hammarstrom M]] | ||
[[Category: Hallberg | [[Category: Hogbom M]] | ||
[[Category: Hammarstrom | [[Category: Holmbergschiavone L]] | ||
[[Category: Hogbom | [[Category: Kotenyova T]] | ||
[[Category: Kotenyova | [[Category: Kursula P]] | ||
[[Category: Kursula | [[Category: Landry R]] | ||
[[Category: Landry | [[Category: Loppnau P]] | ||
[[Category: Loppnau | [[Category: Magnusdottir A]] | ||
[[Category: Magnusdottir | [[Category: Nilsson-Ehle P]] | ||
[[Category: Nilsson-Ehle | [[Category: Nordlund P]] | ||
[[Category: Nordlund | [[Category: Nyman T]] | ||
[[Category: Nyman | [[Category: Ogg D]] | ||
[[Category: Ogg | [[Category: Persson C]] | ||
[[Category: Persson | [[Category: Sagemark J]] | ||
[[Category: Sagemark | [[Category: Schuler H]] | ||
[[Category: Stenmark P]] | |||
[[Category: Schuler | [[Category: Sundstrom M]] | ||
[[Category: Stenmark | [[Category: Thorsell AG]] | ||
[[Category: Sundstrom | [[Category: Uppenberg J]] | ||
[[Category: Thorsell | [[Category: Van Den Berg S]] | ||
[[Category: Uppenberg | [[Category: Wallden K]] | ||
[[Category: | [[Category: Weigelt J]] | ||
[[Category: | |||
[[Category: | |||