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

• DOI: 10.1038/s41467-020-14847-3
• Publication Date: 2020-02-28T11:04:06Z
• Authors: Cyril Dian; Inmaculada Pérez-...; Frédéric Rivière; Thomas Asensio; Pierre Legrand; Markus Ritzefeld; Mengjie Shen; Ernesto Cota; Thierry Meinnel; Edward W. Tate; Carmela Giglione
• Keywords: Mechanism of Action; Transferase

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 snapshots of the entire catalytic mechanism from initial final reaction states. Structural comparisons, together biochemical analysis, provide unforeseen details about how reaches a catalytically competent conformation in which groups are brought into close proximity enable catalysis. We demonstrate that this further supports efficient unprecedented myristoylation lysine side chain, providing evidence NMT acts both as N-terminal-lysine glycine myristoyltransferase.