4f95
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4f95]] is a 1 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=4F95 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4F95 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4f95]] is a 1 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=4F95 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4F95 FirstGlance]. <br> | ||
| - | </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=4f95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f95 OCA], [https://pdbe.org/4f95 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4f95 RCSB], [https://www.ebi.ac.uk/pdbsum/4f95 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4f95 ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.07Å</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=4f95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f95 OCA], [https://pdbe.org/4f95 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4f95 RCSB], [https://www.ebi.ac.uk/pdbsum/4f95 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4f95 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
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== Function == | == 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> | [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> | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | Inosine triphosphate pyrophosphatase (ITPA), a key enzyme involved in maintaining the purity of cellular nucleoside triphosphate pools, specifically recognizes inosine triphosphate and xanthosine triphosphate (including the deoxyribose forms) and detoxifies them by catalyzing the hydrolysis of a phosphoanhydride bond, releasing pyrophosphate. This prevents their inappropriate use as substrates in enzymatic reactions utilizing (d)ATP or (d)GTP. A human genetic polymorphism leads to the substitution of Thr for Pro32 (P32T) and causes ITPA deficiency in erythrocytes, with heterozygotes having on average 22.5% residual activity, and homozygotes having undetectable activity. This polymorphism has been implicated in modulating patients' response to mercaptopurines and ribavirin. Human fibroblasts containing this variant have elevated genomic instability upon treatment with base analogs. We find that the wild-type and P32T forms are dimeric in solution and in the crystal structure. This abolishes the previous speculation that the P32T change disrupts dimerization as a mechanism of inactivation. The only difference in structure from the wild-type protein is that the area surrounding Thr32 is disrupted. Phe31 is flipped from the hydrophobic core out into the solvent, leaving a hole in the hydrophobic core of the protein which likely accounts for the reduced thermal stability of P32T ITPA and ultimately leads to its susceptibility to degradation in human cells. Circular dichroism and thermal denaturation studies confirm these structural results. We propose that the dimer of P32T variant subunit with wild-type subunit is degraded in cells similarly to the P32T homodimer explaining the level of loss of ITPA activity in heterozygotes. | ||
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| - | The human ITPA polymorphic variant P32T is destabilized by the unpacking of the hydrophobic core.,Simone PD, Struble LR, Kellezi A, Brown CA, Grabow CE, Khutsishvili I, Marky LA, Pavlov YI, Borgstahl GE J Struct Biol. 2013 Mar 23. pii: S1047-8477(13)00078-6. doi:, 10.1016/j.jsb.2013.03.007. PMID:23528839<ref>PMID:23528839</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4f95" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Crystal structure of human inosine triphosphate pyrophosphatase P32T variant
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