Anno2015
AutoriCossu, Federica; Milani, Mario; Grassi, Serena; Malvezzi, Francesca; Corti, Alessandro; Bolognesi, Martino; Mastrangelo, Eloise
AbstractInhibitor of Apoptosis Proteins (IAPs) are the target of extensive research in the field of cancer therapy since they regulate apoptosis and cell survival. Smac-mimetics, the most promising IAP-targeting compounds specifically recognize the IAP-BIR3 domain and promote apoptosis, competing with caspases for IAP binding. Furthermore, Smac-mimetics interfere with the NF-B survival pathway, inducing cIAP1 and cIAP2 degradation through an auto-ubiquitination process. It has been shown that the XIAP-BIR1 (X-BIR1) domain is involved in the interaction with TAB1, an upstream adaptor for TAK1 kinase activation, which in turn couples with the NF-B survival pathway. Preventing X-BIR1 dimerization abolishes XIAP-mediated NF-B activation, thus implicating a proximity-induced mechanism for TAK1 activation. In this context, in a systematic search for a molecule capable of impairing X-BIR1/TAB1 assembly, we identified the compound NF023. Here we report the crystal structure of the human X-BIR1 domain in the absence and in the presence of NF023, as a starting concept for the design of novel BIR1-specific compounds acting synergistically with existing pro-apoptotic drugs in cancer therapy. Proteins 2015; 83:612-620. (c) 2015 Wiley Periodicals, Inc.
RivistaProteins (print)
ISSN0887-3585
Impact factor0
Volume83
Pagina inizio612
Pagina fine620
Autori IBFEloise MASTRANGELO, Mario MILANI, Martino BOLOGNESI
Linee di Ricerca IBFMD.P01.005.001
Sedi IBFIBF.MI