title: Protein-protein recognition as a first step towards the inhibition of XIAP and Survivin anti-apoptotic proteins.
abstract: Apoptosis, also called programmed cell death, is a conserved mechanism inherent to all cells that sentences them to death when they receive the appropriate external stimuli. Inhibitor of apoptosis proteins (IAPs) are a family of regulatory proteins that suppress such cell death. XIAP is the most commonly studied member of the IAP family. It binds to and inhibits Caspases, an important family of apoptotic proteases. In addition, XIAP over-expression has been detected in numerous types of cancer. Smac/DIABLO, a mitochondrial protein that binds to IAPs and promotes Caspase activation, has the opposite action to XIAP and can be considered a key protein in the regulation of IAPs. Survivin, the smallest IAP protein, has received a lot of attention due to its specific expression in many cancer cell lines. It has been shown to interact with Smac/DIABLO, even though the structure of this complex has not yet been reported.We analysed the protein-protein interactions appearing in the Smac/DIABLO-XIAP and Smac/DIABLO-Survivin complexes fully, using molecular dynamics simulations. This information is a first step towards the design of Smac/DIABLO peptidomimetics that could be used as innovative therapeutic agents for the treatment of malignancy. Our results complement the experimental interactions described for the first complex and provide a detailed description for the second. We show that Smac/DIABLO interacts in a similar way with both targets through its amino terminal residues. In addition, we identify a pharmacophore formed by eight stable protein-protein interactions for the XIAP complex and seven stable protein-protein interactions for the Survivin complex, which describe the whole contact surface. This information is used to suggest the binding mode of embelin, the first non-peptidic inhibitor of XIAP, and two of its derivatives. Molecular docking and molecular dynamics simulations were also carried out to describe ligand and receptor flexibility. Finally, an MMGBSA protocol was used to obtain a more quantitative description of the binding in all the complexes studied.
authors.affiliation: Department de Química Física, Universitat de Barcelona (UB), Martí i Franqués 1, E-08028 Barcelona, and the Institut de Química Teòrica i Computacional (IQTCUB), Spain.
authors.forename: Cristian
authors.initials: C
authors.lastname: Obiol-Pardo
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Granadino-Roldán
authors.forename: Jaime
authors.initials: J
authors.lastname: Rubio-Martinez
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D016227:Benzoquinones / Q000737:chemistry; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D024101:Mitochondrial Proteins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D055672:Static Electricity; D000077022:Survivin; D013816:Thermodynamics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015032:Zinc / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D016227:Benzoquinones; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; D015032:Zinc; C010945:embelin