2026-05-07T08:16:06Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/42402021-11-10T09:38:19Zcom_10259_3924com_10259_5086com_10259_2604col_10259_3925

Molecular Interactions of Prodiginines with the BH3 Domain of Anti-Apoptotic Bcl-2 Family Members Hossein, Ali Espona Fiedler, Margarita Soto Cerrato, Vanessa Quesada Pato, Roberto Pérez Tomás, Ricardo Guallar, Victor Química orgánica Chemistry, Organic 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 target(s) 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. Spanish government and the European Union (FIS-PI10/00338) and from the ERC-2009-Adg 25027-PELE European project. 2016-09-22T09:02:35Z 2016-09-22T09:02:35Z 2013-02 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 1932-6203 http://hdl.handle.net/10259/4240 10.1371/journal.pone.0057562 eng PLoS ONE. 2013, V. 8, n. 2, e57562 http://dx.doi.org/10.1371/journal.pone.0057562 info:eu-repo/grantAgreement/UE/FIS-PI10/00338 info:eu-repo/grantAgreement/EC/FP7/25027 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf Public Library of Science