8Q23

HsNMT1 in complex with both MyrCoA and Ac-D-ORN-SFSKPR inhibitor peptide

This is a non-PDB format compatible entry.

Summary for 8Q23

• Entry DOI: 10.2210/pdb8q23/pdb
• Descriptor: Glycylpeptide N-tetradecanoyltransferase 1, ACE-ORD-SER-PHE-SER-LYS-PRO-ARG, GLYCEROL, ... (6 entities in total)
• Functional Keywords: e-myristoylation, nmt, myristoyltransferase type1, acyltransferase, gnat, gcn5-related n-acetyltransferases, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 97108.56

Authors

Dian, C.,Giglione, C.,Meinnel, T. (deposition date: 2023-08-01, release date: 2024-08-14, Last modification date: 2025-02-26)

Primary citation

Riviere, F.,Dian, C.,Dutheil, R.F.,Monassa, P.,Giglione, C.,Meinnel, T.
Novel, tightly structurally related N-myristoyltransferase inhibitors display equally potent yet distinct inhibitory mechanisms.
Structure, 32:1737-1750.e3, 2024

PubMed Abstract: N-myristoyltransferases (NMTs) catalyze essential acylations of N-terminal alpha or epsilon amino groups of glycines or lysines. Here, we reveal that peptides tightly fitting the optimal glycine recognition pattern of human NMTs are potent prodrugs relying on a single-turnover mechanism. Sequence scanning of the inhibitory potency of the series closely reflects NMT glycine substrate specificity rules, with the lead inhibitor blocking myristoylation by NMTs of various species. We further redesigned the series based on the recently recognized lysine-myristoylation mechanism by taking advantage of (1) the optimal peptide chassis and (2) lysine side chain mimicry with unnatural enantiomers. Unlike the lead series, the inhibitory properties of the new compounds rely on the protonated state of the side chain amine, which stabilizes a salt bridge with the catalytic base at the active site. Our study provides the basis for designing first-in-class NMT inhibitors tailored for infectious diseases and alternative active site targeting.

PubMed: 39208793
DOI: 10.1016/j.str.2024.08.001

Experimental method

X-RAY DIFFRACTION (1.9 Å)