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: Federica Cossu, Mario Milani, Serena Grassi, Francesca Malvezzi, Alessandro Corti, Martino Bolognesi, Eloise Mastrangelo
• Journal: Proteins (Proteins) Vol. 83 Issue 4 Pg. 612-20 (Apr 2015) ISSN: 1097-0134 [Electronic] United States
• PMID: 25619915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• Inhibitor of Apoptosis Proteins
• NF-kappa B
• NF023
• Recombinant Proteins
• Suramin

Topics

• Crystallization
• Drug Discovery
• Humans
• Inhibitor of Apoptosis Proteins (chemistry, metabolism)
• Molecular Docking Simulation
• NF-kappa B
• Protein Structure, Tertiary
• Recombinant Proteins (chemistry, metabolism)
• Suramin (analogs & derivatives, chemistry, metabolism)