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Human Ribonucleotide Reductase R1 subunit (RRM1) in complex with dATP and Magnesium.

PDB Code 2WGH Target Class Nucleotide metabolism Target RRM1 Alias R1, RIR1, RR1, RRM1 Disease Area/Function cancer Date Deposited Apr 19 2009 Authors M.Welin, M.Moche, C.H.Arrowsmith, H.Berglund, C.Bountra, R.Collins, A.M.Edwards, S.Flodin, A.Flores, S.Graslund, M.Hammarstrom, A. Johansson, I.Johansson, T.Karlberg, T.Kotenyova, T.Nyman, C. Persson, J.Sagemark, H.Schueler, P.Schutz, M.I.Siponen, L.Svensson, A.G.Thorsell, L.Tresaugues, S.Van Den Berg, J.Weigelt, M.Wisniewska, P.Nordlund

About this structure

Ribonucleotide reductase (RNR) catalyses the conversion of ribonucleotides to deoxyribonucleotides. The RNR holo-enzyme consists of a dimer of the large subunit, R1 and a dimer of the small subunit, R2. The catalytic site is situated in the R1 subunit. The reaction is carried out using radical chemistry, where the radical is formed at a di-iron site in the R2 subunit [1]. In DNA synthesis and repair the RNR is a rate-limiting enzyme and inhibition would cause the DNA synthesis to stop [2]. This feature makes it an important drug target for cancer treatment and several drugs are undergoing clinical trials. RNR is allosterically regulated involving two separate sites. The activity site is either stimulated by ATP or inhibited by dATP. The specificity site is regulating the substrate specificity where the effectors are nucleoside triphosphates and the substrates are nucleoside diphosphates [1,3].
Here we have determined the structure of the human R1 subunit to 2.3 Å resolution. The structure was solved with molecular replacement using the structure of the yeast R1 subunit (pdb-code: 1ZYZ) as a search model. The asymmetric unit contained a dimer. The protein was co-crystallized with dATP and Mg which were bound to the specificity site in each subunit of the dimer. Recently the large subunit of yeast RNR and when compared with the human R1 similar structures are revealed with an RMSD of ~ 1Å for 660 residues [4]. The structural knowledge gained from the large subunit of human RNR will aid future design of new agents for cancer therapy.

References

  1. Nordlund P, Reichard P (2006) Ribonucleotide reductases. Annu Rev Biochem. 75:681-706. Review.
  2. Weber G (1983) Biochemical strategy of cancer cells and the design of chemotherapy: G. H. A. Clowes Memorial Lecture. Cancer Res. 1983 Aug;43(8):3466-92.
  3. Reichard P, Eliasson R, Ingemarson R, Thelander L (2000) Cross-talk between the allosteric effector-binding sites in mouse ribonucleotide reductase. J Biol Chem. 2000 Oct 20;275(42):33021-6.
  4. Xu H, Faber C, Uchiki T, Fairman JW, Racca J, Dealwis C (2006) Structures of eukaryotic ribonucleotide reductase I provide insights into dNTP regulation. Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4022-7.