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Molecular basis for allosteric specificity regulation in class Ia ribonucleotide reductase from Escherichia coli

Journal Article · · eLife
DOI:https://doi.org/10.7554/eLife.07141· OSTI ID:1236264
 [1];  [2];  [2];  [2];  [2]
  1. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States); Harvard Univ., Cambridge, MA (United States)
  2. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
+ Show Author Affiliations
Ribonucleotide reductase (RNR) converts ribonucleotides to deoxyribonucleotides, a reaction that is essential for DNA biosynthesis and repair. This enzyme is responsible for reducing all four ribonucleotide substrates, with specificity regulated by the binding of an effector to a distal allosteric site. In all characterized RNRs, the binding of effector dATP alters the active site to select for pyrimidines over purines, whereas effectors dGTP and TTP select for substrates ADP and GDP, respectively. Here, we have determined structures of Escherichia coli class Ia RNR with all four substrate/specificity effector-pairs bound (CDP/dATP, UDP/dATP, ADP/dGTP, GDP/TTP) that reveal the conformational rearrangements responsible for this remarkable allostery. These structures delineate how RNR ‘reads’ the base of each effector and communicates substrate preference to the active site by forming differential hydrogen bonds, thereby maintaining the proper balance of deoxynucleotides in the cell.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
Howard Hughes Medical Inst.; National Inst. of Health; National Science Foundation; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1236264
Journal Information:
eLife, Journal Name: eLife Journal Issue: 2015 Vol. 5; ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (10)

Convergent allostery in ribonucleotide reductase journal June 2019
Effects of T592 phosphomimetic mutations on tetramer stability and dNTPase activity of SAMHD1 can not explain the retroviral restriction defect journal August 2016
Coupled-perturbed DFTB-QM/MM metadynamics: Application to proton-coupled electron transfer journal August 2018
Potent competitive inhibition of human ribonucleotide reductase by a nonnucleoside small molecule journal July 2017
An endogenous dAMP ligand in Bacillus subtilis class Ib RNR promotes assembly of a noncanonical dimer for regulation by dATP journal April 2018
Glutamate 52-β at the α/β subunit interface of Escherichia coli class Ia ribonucleotide reductase is essential for conformational gating of radical transfer journal April 2017
The role of dNTP metabolites in control of the embryonic cell cycle journal September 2019
The Cell Killing Mechanisms of Hydroxyurea journal November 2016
3.3-Å resolution cryo-EM structure of human ribonucleotide reductase with substrate and allosteric regulators bound journal February 2018
Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit journal February 2018

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59 BASIC BIOLOGICAL SCIENCES