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Biophys Chem. 2010 Nov;152(1-3):99-108. doi: 10.1016/j.bpc.2010.08.005. Epub 2010 Aug 17.

Conformational selection, dynamic restriction and the hydrophobic effect coupled to stabilization of the BIR3 domain of the human X-linked inhibitor of apoptosis protein by the tetrapeptide AVPI.

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  • 1Programa de Biologia Estrutural and Centro Nacional de Ressonância Magnética Nuclear de Macromoléculas, Instituto de Bioquímica Médica, Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem, INBEB, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.

Abstract

The XIAP-BIR3 domain blocks a substantial portion of the apoptosis pathway and is an attractive target for novel anticancer agents. The tetrapeptide AVPI, from the protein Smac/DIABLO, binds to the XIAP-BIR3 domain, allowing the cancer cells to die. Here we characterize the binding parameters of AVPI to XIAP-BIR3 and analyze its effects on the thermodynamic stability of this domain. XIAP-BIR3 was exceptionally stable against physical and chemical treatments and became even more stable by interaction with AVPI. Nuclear magnetic resonance experiments demonstrated that conformational selection is taking place upon AVPI interaction with XIAP-BIR3. Molecular dynamics simulations corroborate that the flexibility of XIAP-BIR3 is significantly reduced. The positive binding entropy associated with a loss of conformational entropy involved in the binding indicates that hydrophobic interactions play an important role in the interaction and domain stabilization. The mechanism of XIAP-BIR3 stabilization and its implications for drug affinity optimization are discussed.

Copyright © 2010 Elsevier B.V. All rights reserved.

[PubMed - indexed for MEDLINE]
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