9dws
X-ray crystal structure of Francisella hispaniensis apo ribonucleotide reductase beta subunit
Structural highlights
FunctionPublication Abstract from PubMedRibonucleotide reductases (RNRs) generate 2'-deoxynucleotides for DNA biosynthesis, a reaction essential to all life. Class I RNRs have two subunits, alpha and beta. alpha binds and reduces the substrate, whereas beta oxidizes one of the cysteines in alpha to a C3'-H-bond-cleaving thiyl radical to begin the reaction. The alpha-Cys oxidant in beta is variously a tyrosyl radical (Y(*)) generated by a diiron or dimanganese cluster, a high-valent dimetal cluster [Mn(IV)/Fe(III) or Mn(2)(IV/III)], or a dihydroxylphenylalanine (DOPA) radical that operates without need of a transition metal. The metal (in)dependence of the Cys oxidant in beta correlates loosely with sequence-similarity groupings. We show here that Francisella hispaniensis (Fh) beta, which lies within an uncharacterized sequence cluster that contains orthologs from multiple human pathogens, harbors a Fe(2)(III/III)/Y(*) cofactor, as in class Ia RNRs from eukaryotes and Escherichia coli. Fh beta has several unusual structural features that may reflect adaptation to the bacterium's environment(s). In its apo form, an unwound helix everts a metal ligand toward solvent, and the radical-harboring Y points away from the diiron cluster. An additional aromatic residue (W194), conserved within the sequence cluster, is found close to the universally conserved W37, which is thought to mediate alpha-Cys oxidation in all class I enzymes. The Y(*) in resting beta is remarkably resistant to reduction by hydroxyurea but becomes 8000 times more sensitive when beta is engaged in turnover with alpha. These structural and functional distinctions could be counter measures against host redox defenses that would target the pathogen's RNR and its cofactor. A Structurally Divergent Class Ia Ribonucleotide Reductase from a Tick-Borne Pathogen.,Peduzzi OM, Palowitch GM, Gajewski JP, Hu K, Wheeler A, Laremore TN, Silletti S, Komives EA, Allen BD, Silakov A, Krebs C, Bollinger JM Jr, Lin CY, Boal AK Biochemistry. 2025 Sep 16;64(18):3935-3955. doi: 10.1021/acs.biochem.5c00316. , Epub 2025 Aug 28. PMID:40877217[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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