Architecture of Microcin B17 Synthetase: An Octameric Protein Complex Converting a Ribosomally Synthesized Peptide into a DNA Gyrase Poison

Dmitry Ghilarov, Clare E.M. Stevenson, Dmitrii Y. Travin, Julia Piskunova, Marina Serebryakova, Anthony Maxwell, David M. Lawson, Konstantin Severinov

    Research output: Contribution to journalArticlepeer-review

    26 Citations (Scopus)

    Abstract

    The introduction of azole heterocycles into a peptide backbone is the principal step in the biosynthesis of numerous compounds with therapeutic potential. One of them is microcin B17, a bacterial topoisomerase inhibitor whose activity depends on the conversion of selected serine and cysteine residues of the precursor peptide to oxazoles and thiazoles by the McbBCD synthetase complex. Crystal structures of McbBCD reveal an octameric B 4 C 2 D 2 complex with two bound substrate peptides. Each McbB dimer clamps the N-terminal recognition sequence, while the C-terminal heterocycle of the modified peptide is trapped in the active site of McbC. The McbD and McbC active sites are distant from each other, which necessitates alternate shuttling of the peptide substrate between them, while remaining tethered to the McbB dimer. An atomic-level view of the azole synthetase is a starting point for deeper understanding and control of biosynthesis of a large group of ribosomally synthesized natural products. A topoisomerase inhibitor microcin B17 of Escherichia coli is synthesized from a ribosomally made precursor by conversion of serine and cysteine residues to thiazole and oxazole rings. Ghilarov et al. solved the crystal structure of octameric cyclodehydratase/dehydrogenase complex McbBCD, reconciling data from almost 30 years of studies.

    Original languageEnglish
    Pages (from-to)749-762.e5
    JournalMolecular Cell
    Volume73
    Issue number4
    DOIs
    Publication statusPublished - 21 Feb 2019

    Keywords

    • antibiotic
    • azole synthetase
    • cyclodehydratase
    • dehydrogenase
    • DNA gyrase
    • Escherichia coli microcin B17
    • heterocyclase
    • LAP
    • protein complex crystal structure
    • RiPP

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