Fig. 5.

Strategies to inhibit HECTD3-mediated ubiquitination process. ① Inhibition of the catalytic activity (e.g., heclin). ② Hijacking the E2-binding site (e.g., UbV inhibitor or bicyclic peptides). ③ Interference with the binding of specific substrates. ④ Obstruction of the ubiquitin transthiolation (e.g., clomipramine). ⑤ Interruption of polyubiquitin chain elongation (e.g., occupying the exosite). ⑥ Targeting the HECTD3 posttranslational modification or upstream factors. ⑦ Regulation of the autoinhibition mechanism