Transient pockets on XIAP-BIR2: toward the characterization of putative binding sites of small-molecule XIAP inhibitors |
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Authors: | Susanne Eyrisch Jose L Medina-Franco Volkhard Helms |
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Institution: | 1.Center for Bioinformatics,Saarbruecken,Germany;2.Priaxon AG,München,Germany;3.Torrey Pines Institute for Molecular Studies,Port St. Lucie,USA |
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Abstract: | Protein-protein interactions are abundant in signal transduction pathways and thus of crucial importance in the regulation
of apoptosis. However, designing small-molecule inhibitors for these potential drug targets is very challenging as such proteins
often lack well-defined binding pockets. An example for such an interaction is the binding of the anti-apoptotic BIR2 domain
of XIAP to the pro-apoptotic caspase-3 that results in the survival of damaged cells. Although small-molecule inhibitors of
this interaction have been identified, their exact binding sites on XIAP are not known as its crystal structures reveal no
suitable pockets. Here, we apply our previously developed protocol for identifying transient binding pockets to XIAP-BIR2.
Transient pockets were identified in snapshots taken during four different molecular dynamics simulations that started from
the caspase-3:BIR2 complex or from the unbound BIR2 structure and used water or methanol as solvent. Clustering of these pockets
revealed that surprisingly many pockets opened in the flexible linker region that is involved in caspase-3 binding. We docked
three known inhibitors into these transient pockets and so determined five putative binding sites. In addition, by docking
two inactive compounds of the same series, we show that this protocol is also able to distinguish between binders and nonbinders
which was not possible when docking to the crystal structures. These findings represent a first step toward the understanding
of the binding of small-molecule XIAP-BIR2 inhibitors on a molecular level and further highlight the importance of considering
protein flexibility when designing small-molecule protein-protein interaction inhibitors. |
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