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 B4C2D2 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.
Keywords:
DNA gyrase; Escherichia coli microcin B17; LAP; RiPP; antibiotic; azole synthetase; cyclodehydratase; dehydrogenase; heterocyclase; protein complex crystal structure.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Video-Audio Media
MeSH terms
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Anti-Bacterial Agents / biosynthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Bacterial Proteins / chemistry
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism*
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Bacteriocins / biosynthesis*
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Bacteriocins / chemistry
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Bacteriocins / pharmacology
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Binding Sites
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Crystallography, X-Ray
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Escherichia coli / drug effects
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Escherichia coli / enzymology*
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Escherichia coli / genetics
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Escherichia coli Proteins / chemistry
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Escherichia coli Proteins / genetics
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Escherichia coli Proteins / metabolism*
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Models, Molecular
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Multienzyme Complexes / chemistry
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Multienzyme Complexes / genetics
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Multienzyme Complexes / metabolism*
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Mutation
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Multimerization
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Protein Structure, Quaternary
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Ribosomes / drug effects
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Ribosomes / enzymology*
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Ribosomes / genetics
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Structure-Activity Relationship
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Topoisomerase II Inhibitors / chemistry
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Topoisomerase II Inhibitors / metabolism*
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Topoisomerase II Inhibitors / pharmacology
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X-Ray Diffraction
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Bacteriocins
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Escherichia coli Proteins
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Multienzyme Complexes
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Topoisomerase II Inhibitors
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microcin B17 synthase
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microcin