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

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 ?4?4 rings. Here, we present the first X-ray structure of a gemcitabine-inhibited E. coli RNR and show that the previously described ?4?4 rings can interlock to form an unprecedented (?4?4)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.

SUBMITTER: Zimanyi CM 

PROVIDER: S-EPMC3459064 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature