Different binding modalities of quercetin to inositol-requiring enzyme 1 of S. cerevisiae and human lead to opposite regulation.

ABSTRACT: The flavonoid Quercetin (Qe) was identified as an activator of Inositol-requiring enzyme 1 (IRE1) in S. cerevisiae (scIre1p), but its impact on human IRE1 (hIRE1) remains controversial due to the absence of a conserved Qe binding site. We have explored the binding modes and effect of Qe on both scIre1p and hIRE1 dimers using in silico and in vitro approaches. The activation site in scIre1p stably accommodates both Qe and its derivative Quercitrin (Qi), thus enhancing the stability of the RNase pocket. However, the corresponding region in hIRE1 does not bind any of the two molecules. Instead, we show that both Qe and Qi block the RNase activity of hIRE1 in vitro, with sub-micromolar IC₅₀ values. Our results provide a rationale for why Qe is an activator in scIre1p but a potent in

SUBMITTER: Mahdizadeh SJ 

PROVIDER: S-EPMC10767055 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature