3.3-Å resolution cryo-EM structure of human ribonucleotide reductase with substrate and allosteric regulators bound
Name
elife-31502-v1.pdf
Size
8.6 MB
Format
Adobe PDF
Checksum (MD5)
78fd9494fe1be6ccd4c8fa4f65c6f38e
Author(s)
Brignole, Edward J
Tsai, Kuang-Lei
Chittuluru, Johnathan
Li, Haoran
Aye, Yimon
Penczek, Pawel A
Stubbe, JoAnne
Drennan, Catherine L.
Asturias, Francisco
Date Issued
February 2018
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
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
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution 4.0 International License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.7554/eLife.31502
