Structural basis for precursor protein-directed ribosomal peptide macrocyclization

Journal Article · Fri Nov 11 04:00:00 EST 2016 · Nature Chemical Biology

DOI:https://doi.org/10.1038/nchembio.2200· OSTI ID:1330886

Li, Kunhua ^[1]; Condurso, Heather L. ^[1]; Li, Gengnan ^[1]; Ding, Yousong ^[2]; Bruner, Steven D. ^[1]

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1. Univ. of Florida, Gainesville, FL (United States). Dept. of Chemistry
2. Univ. of Florida, Gainesville, FL (United States). Dept. of Medicinal Chemistry

Macrocyclization is a common feature of natural product biosynthetic pathways including the diverse family of ribosomal peptides. Microviridins are architecturally complex cyanobacterial ribosomal peptides that target proteases with potent reversible inhibition. The product structure is constructed via three macrocyclizations catalyzed sequentially by two members of the ATP-grasp family, a unique strategy for ribosomal peptide macrocyclization. Here we describe in detail the structural basis for the enzyme-catalyzed macrocyclizations in the microviridin J pathway of Microcystis aeruginosa. The macrocyclases MdnC and MdnB interact with a conserved α-helix of the precursor peptide using a novel precursor-peptide recognition mechanism. The results provide insight into the unique protein–protein interactions that are key to the chemistry, suggest an origin for the natural combinatorial synthesis of microviridin peptides, and provide a framework for future engineering efforts to generate designed compounds.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1330886
• Journal Information: Nature Chemical Biology, Journal Name: Nature Chemical Biology Journal Issue: 11 Vol. 12; ISSN 1552-4450
• Publisher: Nature Publishing Group
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES