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

  • Nat Commun. 2020 Feb 28;11(1):1132. doi: 10.1038/s41467-020-14847-3.
Cyril Dian  #  1 ,  Inmaculada Pérez-Dorado  #  2  3  4 ,  Frédéric Rivière  1 ,  Thomas Asensio  1 ,  Pierre Legrand  5 ,  Markus Ritzefeld  2  6 ,  Mengjie Shen  2  7 ,  Ernesto Cota  3 ,  Thierry Meinnel  8 ,  Edward W Tate  9  10 ,  Carmela Giglione  11
Affiliations
  • 1. Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, 91198, France.
  • 2. Department of Chemistry, Imperial College, Molecular Sciences Research Hub, Wood Lane, London, W12 0BZ, UK.
  • 3. Department of Life Sciences, Imperial College London, Exhibition Road, South Kensington, SW7 2AZ, UK.
  • 4. Evotec Ltd, 114 Innovation Dr, Milton Park, Milton, Abingdon, OX14 4RZ, UK.
  • 5. Synchrotron SOLEIL, Gif-sur-Yvette, Cedex, 91192, France.
  • 6. Evotec SE, Essener Bogen 7, Hamburg, 22419, Germany.
  • 7. Oakland Innovation, Mill Rd, Harston, Cambridge, CB22 7GG, UK.
  • 8. Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, 91198, France. [email protected].
  • 9. Department of Chemistry, Imperial College, Molecular Sciences Research Hub, Wood Lane, London, W12 0BZ, UK. [email protected].
  • 10. The Francis Crick Institute, 1 Midland Rd, London, NW 1AT, UK. [email protected].
  • 11. Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, 91198, France. [email protected].
  • # Contributed equally.
PMID: 32111831 DOI: 10.1038/s41467-020-14847-3
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.