Data di Pubblicazione:
2009
Citazione:
Structural Basis for Bivalent Smac-Mimetics Recognition in the IAP Protein Family / F. Cossu, M. Milani, E. Mastrangelo, P. Vachette, F. Servida, D. Lecis, G. Canevari, D. Delia, C. Drago, V. Rizzo, L. Manzoni, P. Seneci, C. Scolastico, M. Bolognesi. - In: JOURNAL OF MOLECULAR BIOLOGY. - ISSN 0022-2836. - 392:3(2009 Sep 25), pp. 630-644.
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
cIAP; inhibition of apoptosis; pro-apoptotic drugs; Smac-DIABLO; XIAP
Elenco autori:
F. Cossu, M. Milani, E. Mastrangelo, P. Vachette, F. Servida, D. Lecis, G. Canevari, D. Delia, C. Drago, V. Rizzo, L. Manzoni, P. Seneci, C. Scolastico, M. Bolognesi
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