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Structure. 2012 Aug 8;20(8):1374-83. doi: 10.1016/j.str.2012.05.009. Epub 2012 Jun 21.

Tangled up in knots: structures of inactivated forms of E. coli class Ia ribonucleotide reductase.

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1
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract

Ribonucleotide reductases (RNRs) provide the precursors for DNA biosynthesis and repair and are successful targets for anticancer drugs such as clofarabine and gemcitabine. Recently, we reported that dATP inhibits E. coli class Ia RNR by driving formation of RNR subunits into α4β4 rings. Here, we present the first X-ray structure of a gemcitabine-inhibited E. coli RNR and show that the previously described α4β4 rings can interlock to form an unprecedented (α4β4)2 megacomplex. This complex is also seen in a higher-resolution dATP-inhibited RNR structure presented here, which employs a distinct crystal lattice from that observed in the gemcitabine-inhibited case. With few reported examples of protein catenanes, we use data from small-angle X-ray scattering and electron microscopy to both understand the solution conditions that contribute to concatenation in RNRs as well as present a mechanism for the formation of these unusual structures.

PMID:
22727814
PMCID:
PMC3459064
DOI:
10.1016/j.str.2012.05.009
[Indexed for MEDLINE]
Free PMC Article

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