Structure-function relationships in assembly of the radical-initiating cofactors of class la-e ribonucleotide reductases

Hannah R. Rose, Gavin M. Palowitch, Kai Hu, Avani Gandhi, Amie K. Boal

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Scopus citations

Abstract

Our updated analysis of class I RNR b subunit structures shows that the newly discovered Id and Ie proteins maintain the overall core fold of the ferritin superfamily (Fig. 17) but modify important features to enable use of novel cofactors and activation mechanisms. The class Id proteins have a severely disrupted core helix 1 to open the metal binding site to solvent, a phenomenon that is necessary for scavenging of superoxide from solution. Interestingly, our search of sequence databases and PDB entries suggests that other uncharacterized systems might share this feature, perhaps as part of a metal-loading mechanism. (Figure Presented). The class Ie enzymes modify their first coordination sphere to enable post-translational modification of a tyrosine (Fig. 18), thereby synthesizing a quinocofactor by an unknown mechanism that likely involves oxidant channeling by a NrdI activase. This subclass was identified by detecting deviations in sequence patterns for predicted ligands, which inspired us to further analyze the conservation and role of second-sphere sites predicted by helix structural patterns. In the Ie enzymes, mutational scanning experiments to link structural features to function showed that several of the core helix first- and second-sphere sites, located at i and i ± 3 or i and i ± 4 (and beyond), are essential for activity.12 For example, in core helix 1, the Gln at i + 3 and the Asp at i + 8 cannot be substituted by any other amino acid. Adaptation of this approach to other class I RNRs could further validate this hypothesis....

Original languageEnglish (US)
Title of host publicationComprehensive Natural Products III
PublisherElsevier
Pages415-441
Number of pages27
ISBN (Electronic)9780081026908
ISBN (Print)9780081026915
DOIs
StatePublished - Jul 22 2020

All Science Journal Classification (ASJC) codes

  • General Chemistry

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