Ribonucleotide Reductases

Cryo-EM structure of dATP-inhibited state of human RNR

Ribonucleotide reductases (RNRs) catalyze an essential step in DNA biosynthesis, the conversion of ribonucleotides to deoxyribonucleotides. RNR inhibition reduces cellular pools of deoxynucleoside triphosphates (dNTPs) consequently impairing DNA biosynthesis and repair. This crucial function has stimulated interest in these enzymes as antitumor, antiviral, and antibacterial drug targets. The Drennan lab uses crystallography, cryo-electron microscopy, and other biophysical and biochemical methods to study class Ia, class II and class III RNRs with the goal of understanding the molecular basis for substrate and inhibitor binding, allosteric regulation, and radical generation/radical transfer.

 

Recent Press

JBC Editor’s Pick with Highlight by Brendon L. Green, Daniel G. Nocera, and JoAnne Stubbe, (2018) “Basis of dATP inhibition of RNRs,” J. Biol. Chem. 293, 10413-10414

MIT News Feb 20, 2018, “Scientists Deliver High-Resolution Glimpse of Enzyme Structure” by Anne Trafton

Forbes.com Feb 26, 2018, “This Tiny Difference Between Human Cells and Bacteria Could Lead to New Antibiotics,” by Fiona McMillan.  

MIT News Jan 12, 2016, “DNA Supply Chain: Chemists Discover How a Single Enzyme Maintains a Cell’s Pool of DNA Building Blocks” by Anne Trafton 

Genetic Engineering & Biotechnology News Jan 13, 2016: “Strange Effector Mechanism Balances Inventory of DNA Building Blocks” 

SpectroscopyNOW.com Jan 15, 2016: “Balancing Building Blocks: RNR Enzyme X-rayed” by David Bradley.

 

Publications (Co-first authors, *Corresponding authors)

Chen, P.Y.-T., Funk, M.A., Brignole, E.J., and Drennan*, C.L. (2018) Disruption of an Oligomeric Interface Prevents Allosteric Inhibition of Escherichia coli class Ia Ribonucleotide Reductase, J. Biol. Chem. 293, 10404-10412. PMCID: In Progress. DOI: 10.1074/jbc.RA118.002569

Brignole, E.J, Tsai, K.-L., Chittuluru, J., Li, H., Aye, Y., Penczek, P.A., Stubbe*, J., Drennan*, C.L. and Asturias*, F. (2018) 3.3-Å Resolution Cryo-EM Structure of Human Ribonucleotide Reductase with Substrate and Allosteric Regulators Bound, eLife 7, e31502.  PMCID: PMC5819950

Lin, Q., Parker, M.J., Taguchi, A.T., Ravichandran, K., Kim, A., Kang, G., Drennan*, C.L., and Stubbe*, J. (2017) Glutamate 52-b at the a/b Subunit Interface of Escherichia coli Class Ia Ribonucleotide Reductase is Essential for Conformational Gating of Radical Transfer, J. Biol. Chem. 292, 9229-9239. PMCID: PMC5454104

Ando*, N., Li, H., Brignole, E.J., Thompson, S., McLaughlin, M.I., Page, J.E., Asturias, F.J., Stubbe, J. and Drennan*, C.L. (2016) Allosteric Inhibition of Human Ribonucleotide Reductase by dATP Entails the Stabilization of a Hexamer, Biochemistry 55, 373-381.  PMCID: PMC4722859

Zimanyi, C.M., Chen, P.Y.-T., Kang, G., Funk, M.A. and Drennan*, C.L. (2016) Molecular Basis for Allosteric Specificity Regulation in Class Ia Ribonucleotide Reductase from Escherichia coli, eLife 5, e07141. PMCID: PMC4728125

Oyala, P.H., Ravichandran, K.R., Funk, M.A., Stucky, P.A., Stich, T.A., Drennan*, C.L., Britt*, R.D., and Stubbe*, J. (2016) Biophysical Characterization of Fluorotyrosine Probes Site-Specifically Incorporated into Enzymes: E. coli Ribonucleotide Reductase as an Example, J. Am. Chem. Soc. 138, 7951–7964.

Wei*, Y., Funk, M.A., Rosado, L.A., Baek, J., Drennan*, C.L., and Stubbe*, J. (2014) The Class III Ribonucleotide Reductase from Neisseria bacilliformis Can Utilize Thioredoxin as a Reductant, Proc. Natl. Acad. Sci. U.S.A. 111, E3756-E3765. PMCID: PMC4246965

Minnihan, E.C., Ando, N., Brignole, E.J., Olshansky, L., Chittuluru, J., Asturias*, F.J., Drennan*, C.L., Nocera*, D.G., and Stubbe*, J. (2013) Generation of a Stable, Aminotyrosyl Radical-Induced α2β2 Complex of Escherichia coli Class Ia Ribonucleotide Reductase, Proc. Natl. Acad. Sci. U.S.A. 110, 3835-3840. PMCID: PMC3593893

Aye, Y., Brignole, E.J., Long, M.J.C., Chittuluru, J., Drennan, C.L., Asturias, F.J., and Stubbe*, J. (2012) Clofarabine Targets the Large Subunit (a) of Human Ribonucleotide Reductase in Live Cells by Assembly into Persistent Hexamers, Chem. Biol. 19, 799-805. PMCID: PMC3408589

Zimanyi, C.M., Ando, N., Brignole, E.J., Asturias, F.J., Stubbe, J., and Drennan*, C.L. (2012) Tangled up in Knots: Structures of Inactivated Forms of E. coli class Ia Ribonucleotide Reductase, Structure 20, 1374-1383. PMCID: PMC3459064

Ando, N., Brignole, E.J., Zimanyi, C.M., Funk, M.A., Yokoyama. K., Asturias, F.J., Stubbe, J. and Drennan*, C.L. (2011) Structural Interconversions Modulate Activity of E. coli Ribonucleotide Reductase, Proc. Natl. Acad. Sci. U.S.A. 108, 21046-21051PMCID: PMC3248520

Sintchak, M.D., Arjara, G., Kellogg, B.A., Stubbe, J., and Drennan*, C.L. (2002) The Crystal Structure of Class II Ribonucleotide Reductase Reveals how an Allosterically Regulated Monomer Mimics a Dimer, Nat. Struct. Biol. 9, 293300. DOI: 10.1038/nsb774 Faculty of 1000 Recommended

 

Review Article

Brignole, E.J., Ando, N., Zimanyi, C.M., and Drennan*, C.L. (2012) The Prototypic Class Ia Ribonucleotide Reductase from Escherichia coli: Still Surprising After All These Years, Biochem. Soc. Trans. 40, 523–530. PMCID: PMC5912335

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