Recognition of Smac-mimetic compounds by the BIR domain of cIAP1

Federica Cossu, Francesca Malvezzi, Giulia Canevari, Eloise Mastrangelo, Daniele Lecis, Domenico Delia, Pierfausto Seneci, Carlo Scolastico, Martino Bolognesi, Mario Milani

Research output: Contribution to journalArticle

Abstract

Inhibitor of apoptosis proteins (IAPs) are negative regulators of apoptosis. As IAPs are overexpressed in many tumors, where they confer chemoresistance, small molecules inactivating IAPs have been proposed as anticancer agents. Accordingly, a number of IAP-binding proapoptotic compounds that mimic the sequence corresponding to the N-terminal tetrapeptide of Smac/DIABLO, the natural endogenous IAPs inhibitor, have been developed. Here, we report the crystal structures of the BIR3 domain of cIAP1 in complex with Smac037, a Smac-mimetic known to bind potently to the XIAP-BIR3 domain and to induce degradation of cIAP1, and in complex with the novel Smac-mimetic compound Smac066. Thermal stability and fluorescence polarization assays show the stabilizing effect and the high affinity of both Smac037 and Smac066 for cIAP1-and cIAP2-BIR3 domains.

Original languageEnglish
Pages (from-to)2418-2429
Number of pages12
JournalProtein Science
Volume19
Issue number12
DOIs
Publication statusPublished - Dec 2010

Keywords

  • Apoptosis
  • BIR3 domain
  • cIAP1
  • IAP family
  • Oncology
  • Smac-mimetics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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    Cossu, F., Malvezzi, F., Canevari, G., Mastrangelo, E., Lecis, D., Delia, D., Seneci, P., Scolastico, C., Bolognesi, M., & Milani, M. (2010). Recognition of Smac-mimetic compounds by the BIR domain of cIAP1. Protein Science, 19(12), 2418-2429. https://doi.org/10.1002/pro.523