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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• 作者：Theo Luiz Ferraz de Souza ; Daniel Sanches ; Rafael Braga Gon&#xe7 ; alves ; Samuel Silva da RochaPita ; Pedro Geraldo Pascutti ; M. Lucia Bianconi ; Fabio Ceneviva Lacerda de Almeida ; Jerson L. Silva ; Andr&#
• 关键词：XIAP-BIR3/AVPI interaction ; Protein stability ; Thermodynamics ; Spectroscopy ; Calorimetry ; Apoptosis
• 刊名：Biophysical Chemistry
• 出版年：2010
• 出版时间：November 2010
• 年：2010
• 卷：152
• 期：1-3
• 页码：99-108
• 全文大小：1440 K

文摘

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.