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Human nudix (nucleoside diphosphate linked moiety X)-type motif 6, C-terminal domain

PDB Code 3H95 Target Class Nucleotide metabolism Target NUDT6 Alias ASFGF2, bFGF, FGF-2, FGF-AS, FGF2AS, gfg, gfg-1, NUDT6 Disease Area/Function cancer Date Deposited Apr 30 2009 Authors Tresaugues, L., Moche, M., Arrowsmith, C.H., Berglund, H., Bountra, C., Collins, R., Edwards, A.M., Flodin, S., Flores, A., Graslund, S., Hammarstrom, M., Johansson, A., Johansson, I., Karlberg, T., Kotyenova, T., Kotzch, A., Nielsen, T.K., Nyman, T., Persson, C., Sagemark, J., Schueler, H., Schutz, P., Siponen, M.I., Svensson, L., Thorsell, A.G., Van Den Berg, S., Weigelt, J., Welin, M., Wisniewska, M., Nordlund, P. Structural Genomics Consortium (SGC) Related Structure 3FXT

About this structure

The expression of fibroblast growth factor 2 (FGF-2) has been shown to be regulated by the mRNA whose DNA matrix is its antisense gene[1]. Both FGF-2 and FGF-2 antisense transcripts overlaps in their 3´ends, thus producing a stable double-stranded RNA duplex [2]. In addition, the FGF-2 antisense gene encodes a 316 amino-acid long protein which belongs to the family of the NUDIX hydrolases, designed under the names of either NUDT6 or GFG. The functions and activity of this protein is only poorly described.
NUDT6 is constituted of two domains: an unknown domain lying between residues 45 and 134 and a NUDIX hydrolase domain encompassing residues 142 to 273.
SGC Stockholm has previously deposited in the PDB the crystallographic structure of the unknown N-terminal domain (PDB entry 3FXT) and now, has solved and refined to 1.7Å resolution the structure of the NUDIX hydrolase domain (PDB entry 3H95). The protein fragment which has produced the crystal used to determinate the structure was encompassing residues 141 to 316 of NUDT6.
The α/β/α sandwich fold typical from NUDIX proteins[3] is present in the structure of the C-terminal of NUDT6. As the N-terminal domain of NUDT6, the NUDIX domain appeared to be dimerical. The dimerisation process involves mainly residues 286 to 301 which make a two-strands extended β-sheet with the monomer of the second subunit. If this example of domain swapping seems to be fairly unique among the Nudix family, the overall conformation of the dimer can be retrieved in some other members of the family as the RNA pyrophosphohydrolase from Bdellovibrio bacteriovirus [4] or the GDP-mannose mannosyl hydrolase [5]. In addition, a citrate anion was found in the putative active site revealing the ability of this pocket to accommodate negatively charged substrates.

References

  1. Li AW, Too CK, Knee R, Wilkinson M and Murphy PR. FGF-2 antisense RNA encodes a nuclear protein with MutT-like antimutator activity Mol Cell Endocrinol, 1997. 133(2): p. 177-82.
  2. Kimelman D and Kirschner MW. An antisense mRNA directs the covalent modification of the transcript encoding fibroblast growth factor in Xenopus oocytes Cell, 1989. 59(4): p. 687-96.
  3. Mildvan AS, Xia Z, Azurmendi HF, Saraswat V, Legler PM, Massiah MA, Gabelli SB, Bianchet MA, Kang LW and Amzel LM. Structures and mechanisms of Nudix hydrolases Arch Biochem Biophys, 2005. 433(1): p. 129-43.
  4. Messing SA, Gabelli SB, Liu Q, Celesnik H, Belasco JG, Pineiro SA and Amzel LM. Structure and biological function of the RNA pyrophosphohydrolase BdRppH from Bdellovibrio bacteriovorus Structure, 2009. 17(3): p. 472-81.
  5. Gabelli SB, Bianchet MA, Azurmendi HF, Xia Z, Sarawat V, Mildvan AS and Amzel LM. Structure and mechanism of GDP-mannose glycosyl hydrolase, a Nudix enzyme that cleaves at carbon instead of phosphorus Structure, 2004. 12(6): p. 927-35.