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High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation

Author

Listed:
  • Cyril Dian

    (Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC))

  • Inmaculada Pérez-Dorado

    (Imperial College, Molecular Sciences Research Hub
    Imperial College London
    Evotec Ltd)

  • Frédéric Rivière

    (Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC))

  • Thomas Asensio

    (Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC))

  • Pierre Legrand

    (Synchrotron SOLEIL)

  • Markus Ritzefeld

    (Imperial College, Molecular Sciences Research Hub
    Evotec SE)

  • Mengjie Shen

    (Imperial College, Molecular Sciences Research Hub
    Oakland Innovation)

  • Ernesto Cota

    (Imperial College London)

  • Thierry Meinnel

    (Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC))

  • Edward W. Tate

    (Imperial College, Molecular Sciences Research Hub
    The Francis Crick Institute)

  • Carmela Giglione

    (Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC))

Abstract

The promising drug target N-myristoyltransferase (NMT) catalyses an essential protein modification thought to occur exclusively at N-terminal glycines (Gly). Here, we present high-resolution human NMT1 structures co-crystallised with reactive cognate lipid and peptide substrates, revealing high-resolution snapshots of the entire catalytic mechanism from the initial to final reaction states. Structural comparisons, together with biochemical analysis, provide unforeseen details about how NMT1 reaches a catalytically competent conformation in which the reactive groups are brought into close proximity to enable catalysis. We demonstrate that this mechanism further supports efficient and unprecedented myristoylation of an N-terminal lysine side chain, providing evidence that NMT acts both as N-terminal-lysine and glycine myristoyltransferase.

Suggested Citation

  • Cyril Dian & Inmaculada Pérez-Dorado & Frédéric Rivière & Thomas Asensio & Pierre Legrand & Markus Ritzefeld & Mengjie Shen & Ernesto Cota & Thierry Meinnel & Edward W. Tate & Carmela Giglione, 2020. "High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14847-3
    DOI: 10.1038/s41467-020-14847-3
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    Cited by:

    1. Diego Rodríguez-Hernández & Kamalakannan Vijayan & Rachael Zigweid & Michael K. Fenwick & Banumathi Sankaran & Wanlapa Roobsoong & Jetsumon Sattabongkot & Elizabeth K. K. Glennon & Peter J. Myler & Pe, 2023. "Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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