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.
Highlights
The promising drug target N-myristoyltransferase (NMT) catalyses an essential protein modification thought to occur exclusively at N-terminal glycines (Gly)
We solved the crystallographic structure of HsNMT1 was crystallised in complex with MyrCoA (HsNMT1) in complex with two different peptides (X and Y; see Methods for peptide details) at 2.3 and 2.1 Å resolution, respectively
We recently reported the crystallographic complex at 2.7 Å resolution of HsNMT1 with a third peptide (Z)[8], which is further analysed here together in light of the X and Y complexes
Summary
The promising drug target N-myristoyltransferase (NMT) catalyses an essential protein modification thought to occur exclusively at N-terminal glycines (Gly). 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-terminallysine and glycine myristoyltransferase. NMTs are thought to transfer a C:14:0 acyl-CoA (MyrCoA) exclusively to the N-terminal glycine (Gly) of specific substrates. Further therapeutic development will be greatly enhanced by a complete understanding of NMT catalysis and substrate selectivity
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