RESUMO
Apoptosis plays an essential role in maintaining cellular homeostasis and preventing cancer progression. Bcl-xL, an anti-apoptotic protein, is an important modulator of the mitochondrial apoptosis pathway and is a promising target for anticancer therapy. In this study, we identified octenidine as a novel Bcl-xL inhibitor through structural feature-based deep learning and molecular docking from a library of approved drugs. The NMR experiments demonstrated that octenidine binds to the Bcl-2 homology 3 (BH3) domain-binding hydrophobic region that consists of the BH1, BH2, and BH3 domains in Bcl-xL. A structural model of the Bcl-xL/octenidine complex revealed that octenidine binds to Bcl-xL in a similar manner to that of the well-known Bcl-2 family protein antagonist ABT-737. Using the NanoBiT protein-protein interaction system, we confirmed that the interaction between Bcl-xL and Bak-BH3 domains within cells was inhibited by octenidine. Furthermore, octenidine inhibited the proliferation of MCF-7 breast and H1299 lung cancer cells by promoting apoptosis. Taken together, our results shed light on a novel mechanism in which octenidine directly targets anti-apoptotic Bcl-xL to trigger mitochondrial apoptosis in cancer cells.
Assuntos
Inteligência Artificial , Iminas/farmacologia , Piridinas/farmacologia , Proteína bcl-X/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Iminas/química , Simulação de Acoplamento Molecular , Neoplasias/patologia , Ligação Proteica/efeitos dos fármacos , Piridinas/química , Proteína Killer-Antagonista Homóloga a bcl-2/química , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína bcl-X/químicaRESUMO
Polymerase η (Polη) is one of the Y-family polymerases that is recruited by monoubiquitinated proliferating cell nuclear antigen (Ub-PCNA) to DNA damage sites during translesion synthesis (TLS). This interaction is mediated by an ubiquitin-binding zinc-finger (UBZ) domain and a PCNA-interacting protein (PIP) box in Polη, which binds to ubiquitin and PCNA, respectively. Here, we show that without the UBZ domain, the PIP box of yeast Polη has a novel binding function with ubiquitin. Furthermore, the UBZ domain and the PIP box share the same binding surfaces for ubiquitin. The interaction with ubiquitin via the PIP box stabilizes the Ub-PCNA/Polη complex. Moreover, the PIP residues I624 and L625 contribute to Polη function in TLS in vivo.
