Molecular Interactions of Prodiginines with the BH3 Domain of Anti-Apoptotic Bcl-2 Family MembersReportar como inadecuado




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Prodigiosin and obatoclax, members of the prodiginines family, are small molecules with anti-cancer properties that are currently under preclinical and clinical trials. The molecular targets of these agents, however, is an open question. Combining experimental and computational techniques we find that prodigiosin binds to the BH3 domain in some BCL-2 protein families, which play an important role in the apoptotic programmed cell death. In particular, our results indicate a large affinity of prodigiosin for MCL-1, an anti-apoptotic member of the BCL-2 family. In melanoma cells, we demonstrate that prodigiosin activates the mitochondrial apoptotic pathway by disrupting MCL-1-BAK complexes. Computer simulations with the PELE software allow the description of the induced fit process, obtaining a detailed atomic view of the molecular interactions. These results provide new data to understand the mechanism of action of these molecules, and assist in the development of more specific inhibitors of anti-apoptotic BCL-2 proteins.



Autor: Ali Hosseini , Margarita Espona-Fiedler , Vanessa Soto-Cerrato, Roberto Quesada, Ricardo Pérez-Tomás, Victor Guallar

Fuente: http://plos.srce.hr/



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