ArticleProceedings of the National Academy of Sciences of the United States of America2006
Structures of eukaryotic ribonucleotide reductase I provide insights into dNTP regulation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 81 citations in OpenAlex.
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- RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.The Journal of clinical investigation · 2022Article
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- Strengths and Weaknesses of Cell Synchronization Protocols Based on Inhibition of DNA Synthesis.International journal of molecular sciences · 2021Review
- Structural determinants and distribution of phosphate specificity in ribonucleotide reductases.The Journal of biological chemistry · 2021Article
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- Genomic Instability in Fungal Plant Pathogens.Genes · 2020Review
- Structures of Class Id Ribonucleotide Reductase Catalytic Subunits Reveal a Minimal Architecture for Deoxynucleotide Biosynthesis.Biochemistry · 2019Article
- A genetic screen pinpoints ribonucleotide reductase residues that sustain dNTP homeostasis and specifies a highly mutagenic type of dNTP imbalance.Nucleic acids research · 2019Article
- An endogenous dAMP ligand inProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Article
- Structure-Guided Synthesis and Mechanistic Studies Reveal Sweetspots on Naphthyl Salicyl Hydrazone Scaffold as Non-Nucleosidic Competitive, Reversible Inhibitors of Human Ribonucleotide Reductase.Journal of medicinal chemistry · 2018Article
- Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit.eLife · 2018Article
- Phylogenetic sequence analysis and functional studies reveal compensatory amino acid substitutions in loop 2 of human ribonucleotide reductase.The Journal of biological chemistry · 2017Article
- Potent competitive inhibition of human ribonucleotide reductase by a nonnucleoside small molecule.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor.The journal of physical chemistry. B · 2016Article
- Expression Pattern Similarities Support the Prediction of Orthologs Retaining Common Functions after Gene Duplication Events.Plant physiology · 2016Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Ribonucleotide reductase catalyzes a crucial step in de novo DNA synthesis and is allosterically controlled by relative levels of dNTPs to maintain a balanced pool of deoxynucleoside triphosphates in the cell. In eukaryotes, the enzyme comprises a heterooligomer of alpha(2) and beta(2) subunits. The alpha subunit, Rnr1, contains catalytic and regulatory sites. Here, we report the only x-ray structures of the eukaryotic alpha subunit of ribonucleotide reductase from Saccharomyces cerevisiae. The structures of the apo-, AMPPNP only-, AMPPNP-CDP-, AMPPNP-UDP-, dGTP-ADP- and TTP-GDP-bound complexes give insight into substrate and effector binding and specificity cross-talk. These are Class I structures with the only fully ordered catalytic sites, including loop 2, a stretch of polypeptide that spans specificity and catalytic sites, conferring specificity. Binding of specificity effector rearranges loop 2; in our structures, this rearrangement moves P294, a residue unique to eukaryotes, out of the catalytic site, accommodating substrate binding. Substrate binding further rearranges loop 2. Cross-talk, by which effector binding regulates substrate preference, occurs largely through R293 and Q288 of loop 2, which are analogous to residues in Thermotoga maritima that mediate cross-talk. However loop-2 conformations and residue-substrate interactions differ substantially between yeast and T. maritima. In most effector-substrate complexes, water molecules help mediate substrate-loop 2 interactions. Finally, the substrate ribose binds with its 3' hydroxyl closer than its 2' hydroxyl to C218 of the catalytic redox pair. We also see a conserved water molecule at the catalytic site in all our structures, near the ribose 2' hydroxyl.
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