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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 DOI Help

Authors: Cyril Dian (Université Paris-Saclay, CEA, CNRS) , Inmaculada Perez-Dorado (Imperial College London) , Frédéric Rivière (Université Paris-Saclay, CEA, CNRS) , Thomas Asensio (Université Paris-Saclay, CEA, CNRS) , Pierre Legrand (Synchrotron SOLEIL) , Markus Ritzefeld (Imperial College London) , Mengjie Shen (Imperial College London) , Ernesto Cota (Imperial College London) , Thierry Meinnel (Université Paris-Saclay, CEA, CNRS) , Edward Tate (Imperial College London; The Francis Crick Institute) , Carmela Giglione (Université Paris-Saclay, CEA, CNRS)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 11

State: Published (Approved)
Published: February 2020
Diamond Proposal Number(s): 12579

Open Access Open Access

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.

Journal Keywords: Chemical modification; Enzyme mechanisms; Proteomics; Transferases; X-ray crystallography

Diamond Keywords: Enzyme

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 27/04/2020 15:27

Documents:
s41467-020-14847-3.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Catalysis Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)