Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 52, Pages 21046-21051Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1112715108
Keywords
allostery; protein-protein interactions; conformational equilibria; nucleotide metabolism
Categories
Funding
- National Science Foundation (NSF)
- National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) via NSF [DMR-0936384]
- NIH/National Center for Research Resources (NCRR) [RR-01646]
- NIH though the NCRR [RR017573]
- Department of Energy (DOE) [DE-AC02-05CH11231]
- DOE
- NIH/NIGMS
- NIH [F32GM904862, F32DK080622, T32GM08334, GM67167, GM29595]
- NSF [0645960]
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Essential for DNA biosynthesis and repair, ribonucleotide reductases (RNRs) convert ribonucleotides to deoxyribonucleotides via radical-based chemistry. Although long known that allosteric regulation of RNR activity is vital for cell health, the molecular basis of this regulation has been enigmatic, largely due to a lack of structural information about how the catalytic subunit (alpha(2)) and the radical-generation subunit (beta(2)) interact. Here we present the first structure of a complex between alpha(2) and beta(2) subunits for the prototypic RNR from Escherichia coli. Using four techniques (small-angle X-ray scattering, X-ray crystallography, electron microscopy, and analytical ultracentrifugation), we describe an unprecedented alpha(4)beta(4) ring-like structure in the presence of the negative activity effector dATP and provide structural support for an active alpha(2)beta(2) configuration. We demonstrate that, under physiological conditions, E. coli RNR exists as a mixture of transient alpha(2)beta(2) and alpha(4)beta(4) species whose distributions are modulated by allosteric effectors. We further show that this interconversion between alpha(2)beta(2) and alpha(4)beta(4) entails dramatic subunit rearrangements, providing a stunning molecular explanation for the allosteric regulation of RNR activity in E. coli.
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