3.3-Å resolution cryo-EM structure of human ribonucleotide reductase with substrate and allosteric regulators bound
Author(s)Brignole, Edward J; Tsai, Kuang-Lei; Chittuluru, Johnathan; Li, Haoran; Aye, Yimon; Penczek, Pawel A; Stubbe, JoAnne; Drennan, Catherine L.; Asturias, Francisco; ... Show more Show less
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Ribonucleotide reductases (RNRs) convert ribonucleotides into deoxyribonucleotides, a reaction essential for DNA replication and repair. Human RNR requires two subunits for activity, the α subunit contains the active site, and the β subunit houses the radical cofactor. Here, we present a 3.3-Å resolution structure by cryo-electron microscopy (EM) of a dATP-inhibited state of human RNR. This structure, which was determined in the presence of substrate CDP and allosteric regulators ATP and dATP, has three α 2 units arranged in an α 6 ring. At near-atomic resolution, these data provide insight into the molecular basis for CDP recognition by allosteric specificity effectors dATP/ATP. Additionally, we present lower-resolution EM structures of human α 6 in the presence of both the anticancer drug clofarabine triphosphate and β 2 . Together, these structures support a model for RNR inhibition in which β 2 is excluded from binding in a radical transfer competent position when α exists as a stable hexamer.
DepartmentMassachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Chemistry
eLife Sciences Publications, Ltd
Brignole, Edward J et al. “3.3-Å Resolution Cryo-EM Structure of Human Ribonucleotide Reductase with Substrate and Allosteric Regulators Bound.” eLife 7 (February 2018): e31502 © Brignole et al
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