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Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain.
- Source :
-
Nature [Nature] 2000 Dec 21-28; Vol. 408 (6815), pp. 1004-8. - Publication Year :
- 2000
-
Abstract
- The inhibitor-of-apoptosis proteins (IAPs) regulate programmed cell death by inhibiting members of the caspase family of enzymes. Recently, a mammalian protein called Smac (also named DIABLO) was identified that binds to the IAPs and promotes caspase activation. Although undefined in the X-ray structure, the amino-terminal residues of Smac are critical for its function. To understand the structural basis for molecular recognition between Smac and the IAPs, we determined the solution structure of the BIR3 domain of X-linked IAP (XIAP) complexed with a functionally active nine-residue peptide derived from the N terminus of Smac. The peptide binds across the third beta-strand of the BIR3 domain in an extended conformation with only the first four residues contacting the protein. The complex is stabilized by four intermolecular hydrogen bonds, an electrostatic interaction involving the N terminus of the peptide, and several hydrophobic interactions. This structural information, along with the binding data from BIR3 and Smac peptide mutants reported here, should aid in the design of small molecules that may be used for the treatment of cancers that overexpress IAPs.
- Subjects :
- Amino Acid Sequence
Antineoplastic Agents chemistry
Apoptosis Regulatory Proteins
Binding Sites
Carrier Proteins chemistry
Caspase 9
Caspase Inhibitors
Cloning, Molecular
Cysteine Proteinase Inhibitors chemistry
Cysteine Proteinase Inhibitors metabolism
Escherichia coli
Humans
Intracellular Signaling Peptides and Proteins
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed
Protein Binding
Protein Structure, Tertiary
Proteins chemistry
Sequence Homology, Amino Acid
Structure-Activity Relationship
X-Linked Inhibitor of Apoptosis Protein
Carrier Proteins metabolism
Mitochondrial Proteins
Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0028-0836
- Volume :
- 408
- Issue :
- 6815
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 11140637
- Full Text :
- https://doi.org/10.1038/35050006