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

• Published in: Nature communications 2020-02, Vol.11 (1), p.1132-1132, Article 1132
• Main Authors: Dian, Cyril, Pérez-Dorado, Inmaculada, Rivière, Frédéric, Asensio, Thomas, Legrand, Pierre, Ritzefeld, Markus, Shen, Mengjie, Cota, Ernesto, Meinnel, Thierry, Tate, Edward W., Giglione, Carmela
• Format: Article
• Language: English
• Subjects: 38/70; 38/79; 631/45/173; 631/45/2783; 631/45/475; 631/45/535/1266; 631/45/607/1172; 82/16; 82/58; 82/80; 82/83; Acylation; Acyltransferases - chemistry; Acyltransferases - genetics; Acyltransferases - metabolism; Biochemical analysis; Catalysis; Catalytic Domain; Coenzyme A - chemistry; Coenzyme A - genetics; Coenzyme A - metabolism; Crystal structure; Crystallography, X-Ray; Glycine; Glycine - metabolism; High resolution; Humanities and Social Sciences; Humans; Kinetics; Life Sciences; Lipids; Lysine; Lysine - metabolism; multidisciplinary; Mutation; Myristic Acid - metabolism; Myristoylation; N-Myristoyltransferase; Peptides; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins; Science; Science (multidisciplinary); Structure-Activity Relationship; Substrate Specificity; Substrates; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• 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. N-terminal glycine myristoyl transferases (NMTs) catalyse the myristoylation of eukaryotic proteins. Here, the authors provide insights into the catalytic mechanism of NMTs by determining the crystal structures of human NMT1 in complex with reactive cognate lipid and peptide substrates and further show that NMT1 also catalyses the acylation of N-terminal lysines.