Structures of eukaryotic ribonucleotide reductase I define gemcitabine diphosphate binding and subunit assembly

Proceedings of the National Academy of Sciences of the United States of America
Hai XuChris Godfrey Dealwis

Abstract

Ribonucleotide reductase (RNR) catalyzes the conversion of nucleoside diphosphates to deoxynucleoside diphosphates. Crucial for rapidly dividing cells, RNR is a target for cancer therapy. In eukaryotes, RNR comprises a heterooligomer of alpha(2) and beta(2) subunits. Rnr1, the alpha subunit, contains regulatory and catalytic sites; Rnr2, the beta subunit (in yeast, a heterodimer of Rnr2 and Rnr4), houses the diferric-tyrosyl radical crucial for catalysis. Here, we present three x-ray structures of eukaryotic Rnr1 from Saccharomyces cerevisiae: one bound to gemcitabine diphosphate (GemdP), the active metabolite of the mechanism-based chemotherapeutic agent gemcitabine; one with an Rnr2-derived peptide, and one with an Rnr4-derived peptide. Our structures reveal that GemdP binds differently from its analogue, cytidine diphosphate; because of unusual interactions of the geminal fluorines, the ribose and base of GemdP shift substantially, and loop 2, which mediates substrate specificity, adopts different conformations when binding to GemdP and cytidine diphosphate. The Rnr2 and Rnr4 peptides, which block RNR assembly, bind differently from each other but have unique modes of binding not seen in prokaryotic RNR. The Rnr2 peptide ado...Continue Reading

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Citations

Jul 25, 2007·Journal of Computer-aided Molecular Design·Ki Hwan Kim
Apr 2, 2011·Nature Reviews. Drug Discovery·Juswinder SinghAdrian Whitty
Jul 26, 2007·Genome Biology·Yong LuZiv Bar-Joseph
May 22, 2008·Genetics·Weimin PengSiavash K Kurdistani
Feb 6, 2007·Proceedings of the National Academy of Sciences of the United States of America·Zhen ZhangMingxia Huang
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Dec 20, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Varsha Gandhi
Nov 2, 2012·Pharmaceuticals·Sanath R WijerathnaChris G Dealwis
Jul 20, 2007·Chemistry : a European Journal·Nuno M F S A CerqueiraMaria J Ramos
Jun 23, 2016·ChemMedChem·Koushik ChandraAssaf Friedler
Jul 19, 2017·Proceedings of the National Academy of Sciences of the United States of America·Md Faiz AhmadChris Godfrey Dealwis

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