http://www.cnr.it/ontology/cnr/individuo/prodotto/ID48408
Structural Basis for Bivalent Smac-Mimetics Recognition in the IAP Protein Family (Articolo in rivista)
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- Structural Basis for Bivalent Smac-Mimetics Recognition in the IAP Protein Family (Articolo in rivista) (literal)
- Anno
- 2009-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1016/j.jmb.2009.04.033 (literal)
- Alternative label
Cossu, Federica; Milani, Mario; Mastrangelo, Eloise; Vachette, Patrice; Servida, Federica; Lecis, Daniele; Canevari, Giulia; Delia, Domenico; Drago, Carmelo; Rizzo, Vincenzo; Manzoni, Leonardo; Seneci, Pierfausto; Scolastico, Carlo; Bolognesi, M (2009)
Structural Basis for Bivalent Smac-Mimetics Recognition in the IAP Protein Family
in Journal of Molecular Biology
(literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- Cossu, Federica; Milani, Mario; Mastrangelo, Eloise; Vachette, Patrice; Servida, Federica; Lecis, Daniele; Canevari, Giulia; Delia, Domenico; Drago, Carmelo; Rizzo, Vincenzo; Manzoni, Leonardo; Seneci, Pierfausto; Scolastico, Carlo; Bolognesi, M (literal)
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- DOI: 10.1016/j.jmb.2009.04.033 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
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- ISI Web of Science (WOS) (literal)
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- Cossu, Federica; Canevari, Giulia; Bolognesi, M, Department of Biomolecular Sciences and Biotechnology - University of Milano,
Servida, Federica; Lecis, Daniele; Delia, Domenico, Istituto Nazionale dei Tumori
Drago, Carmelo; Rizzo, Vincenzo; Seneci, Pierfausto; Scolastico, Carlo; Centro Interdisciplinare Studi bio-molecolari e applicazioni Industriali (CISI) - University of Milano
Vachette, Patrice; Institut de Biochimie et de Biophysique Moléculaire et Cellulaire - Université Paris-Sud
Milani, Mario; Mastrangelo, Eloise, CNR-S3
Manzoni, Leonardo; CNR-ISTM (literal)
- Titolo
- Structural Basis for Bivalent Smac-Mimetics Recognition in the IAP Protein Family (literal)
- Abstract
- XIAP is an apoptotic regulator protein that binds to the effector caspases -3 and -7 through its BIR2 domain, and to initiator caspase-9 through its BIR3 domain. Molecular docking studies suggested that Smac-DIABLO may antagonize XIAP by concurrently targeting both BIR2 and BIR3 domains; on this basis bivalent Smac-mimetic compounds have been proposed and characterized. Here, we report the X-ray crystal structure of XIAP-BIR3 domain in complex with a two-headed compound (compound 3) with improved efficacy relative to its monomeric form. A small-angle X-ray scattering study of XIAP-BIR2BIR3, together with fluorescence polarization binding assays and compound 3 cytotoxicity tests on HL60 leukemia cell line are also reported. The crystal structure analysis reveals a network of interactions supporting XIAP-BIR3/compound 3 recognition; moreover, analytical gel-filtration chromatography shows that compound 3 forms a 1:1 stoichiometric complex with a XIAP protein construct containing both BIR2 and BIR3 domains. On the basis of the crystal structure and small-angle X-ray scattering, a model of the same BIR2-BIR3 construct bound to compound 3 is proposed, shedding light on the ability of compound 3 to relieve XIAP inhibitory effects on caspase-9 as well as caspases -3 and -7. A molecular modeling/docking analysis of compound 3 bound to cIAP1-BIR3 domain is presented, considering that Smac-mimetics have been shown to kill tumor cells by inducing cIAP1 and cIAP2 ubiquitination and degradation. Taken together, the results reported here provide a rationale for further development of compound 3 as a lead in the design of dimeric Smac mimetics for cancer treatment. (C) 2009 Elsevier Ltd. All rights reserved. (literal)
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