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Structures of a non-ribosomal peptide synthetase condensation domain suggest the basis of substrate selectivity

Author

Listed:
  • Thierry Izoré

    (Monash University
    Monash University)

  • Y. T. Candace Ho

    (Monash University
    Monash University
    ARC Centre of Excellence for Innovations in Peptide and Protein Science
    University of Warwick)

  • Joe A. Kaczmarski

    (The Australian National University)

  • Athina Gavriilidou

    (Interfaculty Institute of Microbiology and Infection Medicine Tübingen, Microbiology/Biotechnology, University of Tübingen)

  • Ka Ho Chow

    (The University of Queensland)

  • David L. Steer

    (Monash University
    Monash University)

  • Robert J. A. Goode

    (Monash University
    Monash University)

  • Ralf B. Schittenhelm

    (Monash University
    Monash University)

  • Julien Tailhades

    (Monash University
    Monash University
    ARC Centre of Excellence for Innovations in Peptide and Protein Science)

  • Manuela Tosin

    (University of Warwick)

  • Gregory L. Challis

    (Monash University
    ARC Centre of Excellence for Innovations in Peptide and Protein Science
    University of Warwick
    University of Warwick)

  • Elizabeth H. Krenske

    (The University of Queensland)

  • Nadine Ziemert

    (German Centre for Infection Research (DZIF), Partnersite Tübingen
    Interfaculty Institute for Biomedical Informatics (IBMI), University of Tübingen)

  • Colin J. Jackson

    (ARC Centre of Excellence for Innovations in Peptide and Protein Science
    The Australian National University)

  • Max J. Cryle

    (Monash University
    Monash University
    ARC Centre of Excellence for Innovations in Peptide and Protein Science)

Abstract

Non-ribosomal peptide synthetases are important enzymes for the assembly of complex peptide natural products. Within these multi-modular assembly lines, condensation domains perform the central function of chain assembly, typically by forming a peptide bond between two peptidyl carrier protein (PCP)-bound substrates. In this work, we report structural snapshots of a condensation domain in complex with an aminoacyl-PCP acceptor substrate. These structures allow the identification of a mechanism that controls access of acceptor substrates to the active site in condensation domains. The structures of this complex also allow us to demonstrate that condensation domain active sites do not contain a distinct pocket to select the side chain of the acceptor substrate during peptide assembly but that residues within the active site motif can instead serve to tune the selectivity of these central biosynthetic domains.

Suggested Citation

  • Thierry Izoré & Y. T. Candace Ho & Joe A. Kaczmarski & Athina Gavriilidou & Ka Ho Chow & David L. Steer & Robert J. A. Goode & Ralf B. Schittenhelm & Julien Tailhades & Manuela Tosin & Gregory L. Chal, 2021. "Structures of a non-ribosomal peptide synthetase condensation domain suggest the basis of substrate selectivity," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22623-0
    DOI: 10.1038/s41467-021-22623-0
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