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Structural mechanism of allosteric substrate specificity regulation in a ribonucleotide reductase

Nature Structural & Molecular Biology volume 11, pages 1142–1149 (2004)Cite this article

Abstract

Ribonucleotide reductases (RNRs) catalyze the reduction of ribonucleotides into deoxyribonucleotides, which constitute the precursor pools used for DNA synthesis and repair. Imbalances in these pools increase mutational rates and are detrimental to the cell. Balanced precursor pools are maintained primarily through the regulation of the RNR substrate specificity. Here, the molecular mechanism of the allosteric substrate specificity regulation is revealed through the structures of a dimeric coenzyme B12–dependent RNR from Thermotoga maritima, both in complexes with four effector-substrate nucleotide pairs and in three complexes with only effector. The mechanism is based on the flexibility of loop 2, a key structural element, which forms a bridge between the specificity effector and substrate nucleotides. Substrate specificity is achieved as different effectors and their cognate substrates stabilize specific discrete loop 2 conformations. The mechanism of substrate specificity regulation is probably general for most class I and class II RNRs.

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Figure 1: The structure of the T. maritima (tmNrdJ) dimeric ribonucleotide reductase.
Figure 2: The active site structure of the different substrates in all four cognate substrate–effector complexes.
Figure 3: Effector interactions.
Figure 4: The structural flexibility of loop 2.
Figure 5: Comparison of the regions involved in allosteric specificity regulation in class III and class I-II RNRs.

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Acknowledgements

We thank staff at beamline I711 of MAX-lab (Y. Cerenius) and at the European Molecular Biology Laboratory Hamburg outstation (C. Enroth) for technical help with data collection. This work was supported by grants from the Swedish Research Council (to D.L. and P.N.) and Karolinska Institutet (to P.R.).

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  1. Albert Jordan

    Present address: Centre for Genomic Regulation, Passeig Maritim 37–49, 08003, Barcelona, Spain

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, Stockholm University, Stockholm, S-106 91, Sweden

    Karl-Magnus Larsson & Pär Nordlund

  2. Department of Biochemistry, Karolinska Institute, Stockholm, S-171 77, Sweden

    Albert Jordan, Rolf Eliasson & Peter Reichard

  3. Department of Molecular Biophysics, Lund University, Box 124, Lund, S-221 00, Sweden

    Derek T Logan

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Correspondence to Derek T Logan or Pär Nordlund.

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Larsson, KM., Jordan, A., Eliasson, R. et al. Structural mechanism of allosteric substrate specificity regulation in a ribonucleotide reductase. Nat Struct Mol Biol 11, 1142–1149 (2004). https://doi.org/10.1038/nsmb838

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