ERAP1-IN-1 is an endoplasmic reticulum aminopeptidase 1 (ERAP1) inhibitor. ERAP1-IN-1 competitively inhibits ERAP1 activity towards a nonamer peptide representative of physiological substrates[1].
ERAP1 is an endoplasmic reticulum-resident zinc aminopeptidase that plays an important role in the immune system by trimming peptides for loading onto major histocompatibility complex proteins. ERAP1-IN-1 is an activator of ERAP1 L-AMC hydrolysis and also a very weak inhibitor of ERAP2 with an IC50 greater than 200 μM. ERAP1-IN-1 activated ERAP1 hydrolysis of L-AMC with an AC50 of 3.7 μM and a maximum activity enhancement of 4.1-fold over control. ERAP1-IN-1 inhibited peptide hydrolysis in a dose-dependent manner. Increasing concentrations of ERAP1-IN-1 resulted in increased rather than decreased L-pNA hydrolysis activity, across a range of substrate concentrations indicating that ERAP1-IN-1 is acting as a non-essential activator of L-pNA hydrolysis. ERAP1-IN-1 exhibited specific inhibition of ERAP1 in the cellular context with an IC50 of 1 μM. ERAP1-IN-1 activated all three ERAP1 alleles but was a more potent activator of disease-associated allele II, which it activated with sub-micromolar AC50[2].
作用机制
For ERAP1-IN-1, the top in silico docking solutions outside the active site were found at the junction of domains II and IV[2].
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