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

Cyril Dian, Inmaculada Pérez-Dorado, Frédéric Rivière, Thomas Asensio, Pierre Legrand, Markus Ritzefeld, Mengjie Shen, Ernesto Cota, Thierry Meinnel (), Edward W. Tate () and Carmela Giglione ()
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Cyril Dian: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Inmaculada Pérez-Dorado: Imperial College, Molecular Sciences Research Hub
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
Mengjie Shen: Imperial College, Molecular Sciences Research Hub
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
Carmela Giglione: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14847-3

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DOI: 10.1038/s41467-020-14847-3

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