2j4e: Difference between revisions
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==Overview== | ==Overview== | ||
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. | 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. | ||
==Disease== | |||
Known disease associated with this structure: Inosine triphosphatase deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=147520 147520]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: nucleotide metabolism]] | [[Category: nucleotide metabolism]] | ||
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Revision as of 23:45, 12 November 2007
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THE ITP COMPLEX OF HUMAN INOSINE TRIPHOSPHATASE
OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Inosine triphosphatase deficiency OMIM:[147520]
About this StructureAbout this Structure
2J4E is a Single protein structure of sequence from Homo sapiens with MG, ITT, POP and IMP as ligands. Active as Nucleoside-triphosphate diphosphatase, with EC number 3.6.1.19 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
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
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OCA- Pages with broken file links
- Homo sapiens
- Nucleoside-triphosphate diphosphatase
- Single protein
- Arrowsmith, C.
- Berg, S.Van.Den.
- Berglund, H.
- Busam, R.
- Collins, R.
- Edwards, A.
- Ehn, M.
- Flodin, S.
- Flores, A.
- Graslund, S.
- Hallberg, B.M.
- Hammarstrom, M.
- Hogbom, M.
- Kotenyova, T.
- Kursula, P.
- Landry, R.
- Loppnau, P.
- Magnusdottir, A.
- Nilsson-Ehle, P.
- Nordlund, P.
- Nyman, T.
- Ogg, D.
- Persson, C.
- Sagemark, J.
- Schiavone, L.Holmberg.
- Schuler, H.
- Stenmark, P.
- Sundstrom, M.
- Thorsell, A.G.
- Uppenberg, J.
- Wallden, K.
- Weigelt, J.
- IMP
- ITT
- MG
- POP
- Disease mutation
- Hydrolase
- Imp
- Inosine triphosphatase deficiency
- Inosine triphosphate pyrophosphohydrolase
- Itp
- Nucleotide metabolism