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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / chemistry*
  • Acyltransferases / genetics
  • Acyltransferases / metabolism*
  • Catalysis
  • Catalytic Domain
  • Coenzyme A / chemistry
  • Coenzyme A / genetics
  • Coenzyme A / metabolism
  • Crystallography, X-Ray
  • Glycine / metabolism*
  • Humans
  • Kinetics
  • Lysine / metabolism*
  • Mutation
  • Myristic Acid / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Substrate Specificity


  • Myristic Acid
  • Acyltransferases
  • glycylpeptide N-tetradecanoyltransferase
  • Lysine
  • Coenzyme A
  • Glycine