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NF023 binding to XIAP‐BIR1: Searching drugs for regulation of the NF‐κB pathway
Author(s) -
Cossu Federica,
Milani Mario,
Grassi Serena,
Malvezzi Francesca,
Corti Alessandro,
Bolognesi Martino,
Mastrangelo Eloise
Publication year - 2015
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24766
Subject(s) - xiap , microbiology and biotechnology , inhibitor of apoptosis , chemistry , signal transducing adaptor protein , context (archaeology) , apoptosis , nf κb , ubiquitin , kinase , signal transduction , cancer research , biology , caspase , programmed cell death , biochemistry , paleontology , gene
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. Proteins 2015; 83:612–620. © 2015 Wiley Periodicals, Inc.