2CAR

Crystal Structure Of Human Inosine Triphosphatase

2CAR の概要

• エントリーDOI: 10.2210/pdb2car/pdb
• 分子名称: INOSINE TRIPHOSPHATE PYROPHOSPHATASE (2 entities in total)
• 機能のキーワード: hydrolase, inosine triphosphate pyrophosphohydrolase, inosine triphosphatase deficiency, itp, imp, disease mutation, nucleotide metabolism
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43225.51

構造登録者

Stenmark, P.,Kursula, P.,Arrowsmith, C.,Berglund, H.,Edwards, A.,Ehn, M.,Flodin, S.,Flores, A.,Graslund, S.,Hammarstrom, M.,Hallberg, B.M.,Hogbom, M.,Holmberg Schiavone, L.,Kotenyova, T.,Nilsson-Ehle, P.,Nyman, T.,Ogg, D.,Persson, C.,Sagemark, J.,Schuler, H.,Sundstrom, M.,Thorsell, A.G.,van den Berg, S.,Weigelt, J.,Nordlund, P. (登録日: 2005-12-22, 公開日: 2006-01-04, 最終更新日: 2023-12-13)

主引用文献

Stenmark, P.,Kursula, P.,Flodin, S.,Graslund, S.,Landry, R.,Nordlund, P.,Schuler, H.
Crystal Structure of Human Inosine Triphosphatase. Substrate Binding and Implication of the Inosine Triphosphatase Deficiency Mutation P32T.
J.Biol.Chem., 282:3182-, 2007

PubMed Abstract: 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.

PubMed: 17138556
DOI: 10.1074/JBC.M609838200

実験手法

X-RAY DIFFRACTION (1.09 Å)