2j4e: Difference between revisions
No edit summary |
No edit summary |
||
| Line 5: | Line 5: | ||
==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, .. | 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. | ||
==About this Structure== | ==About this Structure== | ||
2J4E is a | 2J4E is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, ITT, POP and IMP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Nucleoside-triphosphate_diphosphatase Nucleoside-triphosphate diphosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.1.19 3.6.1.19] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2J4E OCA]. | ||
==Reference== | ==Reference== | ||
| Line 59: | Line 59: | ||
[[Category: nucleotide metabolism]] | [[Category: nucleotide metabolism]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 14:57:17 2007'' | ||
Revision as of 15:51, 5 November 2007
|
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.
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
Page seeded by OCA on Mon Nov 5 14:57:17 2007
Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
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