title: Molecular interactions of prodiginines with the BH3 domain of anti-apoptotic Bcl-2 family members.
abstract: 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.
authors: Joint BSC-IRB Research Program in Computational Biology, Barcelona, Spain.
authors: Ali
authors: A
authors: Hosseini
authors: Margarita
authors: M
authors: Espona-Fiedler
authors: Vanessa
authors: V
authors: Soto-Cerrato
authors: Roberto
authors: R
authors: Quesada
authors: Ricardo
authors: R
authors: Pérez-Tomás
authors: Victor
authors: V
authors: Guallar
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D008928:Mitochondria / Q000378:metabolism; D062105:Molecular Docking Simulation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: D008024:Ligands; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; C010307:prodiginine; D011353:Prodigiosin