title: NF023 binding to XIAP-BIR1: searching drugs for regulation of the NF-κB pathway.
abstract: Inhibitor 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-κB 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-κB survival pathway. Preventing X-BIR1 dimerization abolishes XIAP-mediated NF-κB 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.
authors.affiliation: Dipartimento Di Bioscienze, Università Di Milano, I-20133, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cossu
authors.forename: Mario
authors.initials: M
authors.lastname: Milani
authors.forename: Serena
authors.initials: S
authors.lastname: Grassi
authors.forename: Francesca
authors.initials: F
authors.lastname: Malvezzi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corti
authors.forename: Martino
authors.initials: M
authors.lastname: Bolognesi
authors.forename: Eloise
authors.initials: E
authors.lastname: Mastrangelo
mesh_terms: D003460:Crystallization; D055808:Drug Discovery; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry* / Q000378:metabolism*; D062105:Molecular Docking Simulation; D016328:NF-kappa B; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013498:Suramin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C105374:NF023; D011994:Recombinant Proteins; D013498:Suramin
keywords: BIR; NF-κB; XIAP; in silico docking; protein structure