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Human Ribonucleotide reductase, subunit M2

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PDB Code 2VUX Target Class Nucleotide metabolism Target RRM2B Alias DKFZp686M05248, MGC102856, MGC42116, p53R2, RRM2B Disease Area/Function metabolism, cancer Date Deposited May 31 2008 Authors M.WELIN, M.MOCHE, J.ANDERSSON, C.H.ARROWSMITH, H.BERGLUND, R.D.BUSAM, R.COLLINS, L.G.DAHLGREN, A.M.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, M.D.HERMAN, A.JOHANSSON, I.JOHANSSON, A.KALLAS, T.KARLBERG, T.KOTENYOVA, L.LEHTIO, M.E.NILSSON, T.NYMAN, C.PERSSON, J.SAGEMARK, H.SCHUELER, L.SVENSSON, A.G.THORSELL, L.TRESAUGUES, S.VAN DEN BERG, J.WEIGELT, M.WIKSTROM, P.NORDLUND

About this structure

RRM2B (EC 1.17.4.1) is a homolog of the small ribonucleotide reductase, R2 subunit. Ribonucleotide reductase (RNR) catalyses the conversion of ribonucleotides to deoxyribonucleotides. The reaction is carried out using radical chemistry. The radical is formed at a di-iron site in the R2 subunit; stored as a tyrosyl radical and delivered to the R1 catalytic site when needed for catalysis. In DNA synthesis RNR is a rate-limiting enzyme and inhibition would lead to that the DNA synthesis stops. This feature makes it an important drug target for cancer treatment. RRM2B is induced by the tumor suppressor protein p53 and is thus also called p53R2. It forms an active (RNR) complex with RRM1 which is expressed both in resting and proliferating cells in response to DNA damage. RRM2B is ~ 80% identical to R2, but lacks part of the N-terminal [1]. The N-terminal of R2 includes a KEN box sequence required for degradation during mitosis whereas this box is absent in p53R2 [2]. Knockout studies from mice have shown that RRM2B is essential for cell survival. Recently it was demonstrated that there is a correlation between mutations in RRM2B and the severe muscle mitochondrial DNA depletion syndrome [3].

Crystals were obtained in the presence of chymotrypsin diffracting to 2.8 Å. The structure has been solved using molecular replacement using the structure of the human R2 subunit (pdb-code: 2UW2) as a search model. There is only one iron bound to the di-iron site located in the middle of a four helix bundle. The asymmetric unit contains the dimer of the RRM2B. A stretch of six residues in the middle of the helix containing the aspartic acid 100, which normally binds the second iron, is partly missing in the structure of RRM2B.

References

  1. Nordlund P, Reichard P. Annu Rev Biochem. 2006;75:681-706.
  2. Chabes AL et. al. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3925-9.
  3. Bourdon A et. al. Nat Genet. 2007 Jun;39(6):776-80.