signature=e57ac999ed4ba611c1eee439ed599d1d,NMR studies reveal an unexpected binding site for a redox...

摘要：

AP endonuclease 1 (APE1) is a multifaceted protein with essential roles in DNA repair and transcriptional regulation. APE1 (ref-1) activates many transcription factors (TF), including AP-1 and NF-κB. While the mechanism of APE1 redox activity remains unknown, it may involve reduction of an oxidized Cys in the TF DNA-binding domain. Several small molecules inhibit APE1-mediated TF activation, including the quinone derivative E3330. It has been proposed some inhibitors bind near C65, a residue suggested to be important for TF activation, but the binding site has not been determined for any inhibitor. Remarkably, NMR and molecular docking studies here reveal E3330 binds in the DNA repair active site of APE1, far removed from C65. Accordingly, AP endonuclease activity is substantially inhibited by E3330 (100 μM), suggesting that E3330 may not selectively inhibit APE1 redox activity in cells, in contrast with previous proposals. A naphthoquinone analogue of E3330, RN7-60, binds a site removed from both C65 and...

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