Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-14847-3
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Funding
- MMV [15-0054]
- Cancer Research UK [C29637/A20183]
- 7th Framework Programme of the European Union [PIEF-GA-2013-623648]
- ANR PalMyProt grant [ANR-2010-BLAN-1611-01]
- Labex Saclay Plant Sciences-SPS [ANR-10-LABX-0040-SPS]
- FRISBI [ANR-10-INSB-05-01]
- IBiSA
- Ile de France Region
- Plan Cancer
- Paris-Sud University
- PhD fellowship ARDoc program from Region Ile-de-France [17012695]
- CNRS
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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.
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