Structure and function analysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP)

Biochemistry. 2003 Jul 15;42(27):8223-31. doi: 10.1021/bi034227t.


Melanoma inhibitor of apoptosis (ML-IAP) is a potent anti-apoptotic protein that is upregulated in a number of melanoma cell lines but not expressed in most normal adult tissues. Overexpression of IAP proteins, such as ML-IAP or the ubiquitously expressed X-chromosome-linked IAP (XIAP), in human cancers has been shown to suppress apoptosis induced by a variety of stimuli. Peptides based on the processed N-terminus of Smac/DIABLO can negate the ability of overexpressed ML-IAP or XIAP to suppress drug-induced apoptosis. Such peptides have been demonstrated to bind to the single baculovirus IAP repeat (BIR) of ML-IAP and the third BIR of XIAP with similar high affinities (approximately 0.5 microM). Herein, we use phage-display of naïve peptide libraries and synthetic peptides to investigate the peptide-binding properties of ML-IAP-BIR and XIAP-BIR3. X-ray crystal structures of ML-IAP-BIR in complex with Smac- and phage-derived peptides, together with peptide structure-activity-relationship data, indicate that the peptides can be modified to provide increased binding affinity and selectivity for ML-IAP-BIR relative to XIAP-BIR3. For instance, substitution of Pro3' in the Smac-based peptide (AVPIAQKSE) with (2S,3S)-3-methylpyrrolidine-2-carboxylic acid [(3S)-methyl-proline] results in a peptide with 7-fold greater affinity for ML-IAP-BIR and about 100-fold specificity for ML-IAP-BIR relative to XIAP-BIR3.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Crystallography, X-Ray
  • Genetic Linkage
  • Inhibitor of Apoptosis Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasm Proteins / chemistry*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship
  • X Chromosome


  • Adaptor Proteins, Signal Transducing
  • BIRC7 protein, human
  • Carrier Proteins
  • Inhibitor of Apoptosis Proteins
  • Neoplasm Proteins

Associated data

  • PDB/1OXN
  • PDB/1OXQ
  • PDB/1OY7