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Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain

Z Liu1, C Sun, E T Olejniczak

  • 1Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.

Nature
|January 5, 2001
PubMed

Insights

Smac (DIABLO) binding to inhibitor-of-apoptosis proteins (IAPs) is crucial for activating caspases. This study reveals the structure of a Smac peptide bound to the BIR3 domain of XIAP, aiding cancer therapy development.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Background:

  • Inhibitor-of-apoptosis proteins (IAPs) are key regulators of programmed cell death, inhibiting caspases.
  • Smac (DIABLO) antagonizes IAPs, promoting caspase activation and apoptosis.
  • The N-terminal residues of Smac are essential for its function, but their structural role in IAP binding is unclear.

Purpose of the Study:

  • To elucidate the structural basis of molecular recognition between Smac and IAPs.
  • To determine the solution structure of the BIR3 domain of XIAP complexed with a Smac-derived peptide.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy to determine the solution structure.
  • Site-directed mutagenesis to analyze Smac peptide and XIAP BIR3 domain interactions.

Main Results:

  • The nine-residue Smac peptide adopts an extended conformation, binding across the third beta-strand of the XIAP BIR3 domain.
  • Only the N-terminal four residues of the Smac peptide directly interact with the BIR3 domain.
  • The complex is stabilized by hydrogen bonds, electrostatic interactions, and hydrophobic interactions.

Conclusions:

  • The determined structure provides critical insights into Smac-IAP molecular recognition.
  • This structural information can guide the design of small molecules targeting IAPs for cancer therapy.

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