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Title: Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization

Abstract

Ribonucleotide reductase (RR) is an {alpha}{sub n}{beta}{sub n} (RR1-RR2) complex that maintains balanced dNTP pools by reducing NDPs to dNDPs. RR1 is the catalytic subunit, and RR2 houses the free radical required for catalysis. RR is allosterically regulated by its activator ATP and its inhibitor dATP, which regulate RR activity by inducing oligomerization of RR1. Here, we report the first X-ray structures of human RR1 bound to TTP alone, dATP alone, TTP-GDP, TTP-ATP, and TTP-dATP. These structures provide insights into regulation of RR by ATP or dATP. At physiological dATP concentrations, RR1 forms inactive hexamers. We determined the first X-ray structure of the RR1-dATP hexamer and used single-particle electron microscopy to visualize the {alpha}{sub 6}-{beta}{beta}'-dATP holocomplex. Site-directed mutagenesis and functional assays confirm that hexamerization is a prerequisite for inhibition by dATP. Our data indicate a mechanism for regulating RR activity by dATP-induced oligomerization.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ;  [1];  [2];  [2];  [2]
  1. (Case Western)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
FOREIGNNIH
OSTI Identifier:
1020571
Resource Type:
Journal Article
Journal Name:
Nat. Struct. Mol. Biol.
Additional Journal Information:
Journal Volume: 18; Journal Issue: (3) ; 03, 2011; Journal ID: ISSN 1545-9993
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; CATALYSIS; ELECTRON MICROSCOPY; FUNCTIONALS; MUTAGENESIS; OXIDOREDUCTASES; RADICALS; REGULATIONS

Citation Formats

Fairman, James Wesley, Wijerathna, Sanath Ranjan, Ahmad, Md Faiz, Xu, Hai, Nakano, Ryo, Jha, Shalini, Prendergast, Jay, Welin, R. Martin, Flodin, Susanne, Roos, Annette, Nordlund, Pär, Li, Zongli, Walz, Thomas, Dealwis, Chris Godfrey, Harvard-Med), Karolinska), and Tennessee-K). Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization. United States: N. p., 2011. Web. doi:10.1038/nsmb.2007.
Fairman, James Wesley, Wijerathna, Sanath Ranjan, Ahmad, Md Faiz, Xu, Hai, Nakano, Ryo, Jha, Shalini, Prendergast, Jay, Welin, R. Martin, Flodin, Susanne, Roos, Annette, Nordlund, Pär, Li, Zongli, Walz, Thomas, Dealwis, Chris Godfrey, Harvard-Med), Karolinska), & Tennessee-K). Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization. United States. doi:10.1038/nsmb.2007.
Fairman, James Wesley, Wijerathna, Sanath Ranjan, Ahmad, Md Faiz, Xu, Hai, Nakano, Ryo, Jha, Shalini, Prendergast, Jay, Welin, R. Martin, Flodin, Susanne, Roos, Annette, Nordlund, Pär, Li, Zongli, Walz, Thomas, Dealwis, Chris Godfrey, Harvard-Med), Karolinska), and Tennessee-K). Mon . "Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization". United States. doi:10.1038/nsmb.2007.
@article{osti_1020571,
title = {Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization},
author = {Fairman, James Wesley and Wijerathna, Sanath Ranjan and Ahmad, Md Faiz and Xu, Hai and Nakano, Ryo and Jha, Shalini and Prendergast, Jay and Welin, R. Martin and Flodin, Susanne and Roos, Annette and Nordlund, Pär and Li, Zongli and Walz, Thomas and Dealwis, Chris Godfrey and Harvard-Med) and Karolinska) and Tennessee-K)},
abstractNote = {Ribonucleotide reductase (RR) is an {alpha}{sub n}{beta}{sub n} (RR1-RR2) complex that maintains balanced dNTP pools by reducing NDPs to dNDPs. RR1 is the catalytic subunit, and RR2 houses the free radical required for catalysis. RR is allosterically regulated by its activator ATP and its inhibitor dATP, which regulate RR activity by inducing oligomerization of RR1. Here, we report the first X-ray structures of human RR1 bound to TTP alone, dATP alone, TTP-GDP, TTP-ATP, and TTP-dATP. These structures provide insights into regulation of RR by ATP or dATP. At physiological dATP concentrations, RR1 forms inactive hexamers. We determined the first X-ray structure of the RR1-dATP hexamer and used single-particle electron microscopy to visualize the {alpha}{sub 6}-{beta}{beta}'-dATP holocomplex. Site-directed mutagenesis and functional assays confirm that hexamerization is a prerequisite for inhibition by dATP. Our data indicate a mechanism for regulating RR activity by dATP-induced oligomerization.},
doi = {10.1038/nsmb.2007},
journal = {Nat. Struct. Mol. Biol.},
issn = {1545-9993},
number = (3) ; 03, 2011,
volume = 18,
place = {United States},
year = {2011},
month = {7}
}