Z-VAE(OMe)-FMK

Z-VAE (OMe)-FMK is a selective inhibitor of UCHL1, with better selectivity over UCHL3 and UCHL5. Z-VAE (OMe)-FMK binds to the active site cleft, covalently modifies the active site cysteine C90 to form a thioether bond, binds to inactive UCHL1 with a misaligned catalytic triad, and acts via a two-step addition-folding/migration/displacement mechanism. Z-VAE (OMe)-FMK stabilizes interactions through hydrogen bonding with oxyanion hole residues and van der Waals interactions with surrounding residues. Z-VAE (OMe)-FMK can be used in research related to colorectal cancer, lung cancer, pancreatic cancer, and Alzheimer's disease^[1][2]. In Vitro:Z-VAE(OMe)-FMK (100 μM) irreversibly inhibits purified recombinant UCHL1 by covalently modifying active-site Cys90, binds to the enzyme's inactive, misaligned catalytic triad conformation, and does not inhibit purified recombinant UCHL3 or UCHL5 at the same concentration^[1].
Z-VAE(OMe)-FMK binds covalently and specifically to the active site of purified UCH-L1 protein via interactions with residues C90, S89, N88, Q84, N159, R178, and M6, as observed in a 2.35 Å resolution co-crystal structure^[2].