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

Fairman JW, Wijerathna SR, Ahmad MF, Xu H, Nakano R, Jha S, Prendergast J, Welin RM, Flodin S, Roos A, Nordlund P, Li Z, Walz T, Dealwis CG
Nat Struct Mol Biol 18 316-22 (2011)
Related entries: 2wgh, 3hnc, 3hnd, 3hne, 3hnf

Cited: 109 times
EuropePMC logo PMID: 21336276

Abstract

Ribonucleotide reductase (RR) is an α(n)β(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 α(6)-ββ'-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.

Reviews - 3paw mentioned but not cited (1)

  1. Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present. Huff SE, Winter JM, Dealwis CG. Biomolecules 12 815 (2022)

Articles - 3paw mentioned but not cited (5)

  1. Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization. Fairman JW, Wijerathna SR, Ahmad MF, Xu H, Nakano R, Jha S, Prendergast J, Welin RM, Flodin S, Roos A, Nordlund P, Li Z, Walz T, Dealwis CG. Nat. Struct. Mol. Biol. 18 316-322 (2011)
  2. Allosteric Inhibition of Human Ribonucleotide Reductase by dATP Entails the Stabilization of a Hexamer. Ando N, Li H, Brignole EJ, Thompson S, McLaughlin MI, Page JE, Asturias FJ, Stubbe J, Drennan CL. Biochemistry 55 373-381 (2016)
  3. Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators. Ahmad MF, Huff SE, Pink J, Alam I, Zhang A, Perry K, Harris ME, Misko T, Porwal SK, Oleinick NL, Miyagi M, Viswanathan R, Dealwis CG. J. Med. Chem. 58 9498-9509 (2015)
  4. 3.3-Å resolution cryo-EM structure of human ribonucleotide reductase with substrate and allosteric regulators bound. Brignole EJ, Tsai KL, Chittuluru J, Li H, Aye Y, Penczek PA, Stubbe J, Drennan CL, Asturias F. Elife 7 (2018)
  5. A fluorimetric readout reporting the kinetics of nucleotide-induced human ribonucleotide reductase oligomerization. Fu Y, Lin H, Wisitpitthaya S, Blessing WA, Aye Y. Chembiochem 15 2598-2604 (2014)


Reviews citing this publication (23)

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Articles citing this publication (80)

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