High resolution snapshot – N-myristoyltransferase (NMT) in action
In humans there are two genes and isoforms for NMT (NMT1 and NMT2) which have very similar sequences in their catalytic domain; it is not yet known if they have distinct roles in the cell. Myricx is focused on developing inhibitors against both.
Along with our collaborators, we have taken a series of structural snapshots of NMT1 at high resolution which revealed the exact conformation of the enzymes active region during the entire catalysis process. These structures, generated by X-ray crystallography, involved co-crystallising the enzyme with reactive lipid and peptide substrates to clarify exactly how myristoylation occurs, and how the peptide/protein substrate is modified.
This study revealed unforeseen details about how NMT1 reaches a conformation in which the reactive groups are brought into close proximity to enable catalysis. It also demonstrated 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 (Dian et al 2020).
This unique structural and conformational insight is critical for the development of new chemical inhibitors of NMT1, with potential to impact numerous medical conditions including cancer.