1OXN

Structure and Function Analysis of Peptide Antagonists of Melanoma Inhibitor of Apoptosis (ML-IAP)

Summary for 1OXN

• Entry DOI: 10.2210/pdb1oxn/pdb
• Related: 1OXQ 1OY7
• Descriptor: Baculoviral IAP repeat-containing protein 7, AEAVPWKSE peptide, ZINC ION, ... (5 entities in total)
• Functional Keywords: zinc binding, peptide complex, apoptosis inhibition, apoptosis-peptide complex, apoptosis/peptide
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q96CA5
• Total number of polymer chains: 6
• Total formula weight: 80417.59

Authors

Franklin, M.C.,Kadkhodayan, S.,Ackerly, H.,Alexandru, D.,Distefano, M.D.,Elliott, L.O.,Flygare, J.A.,Vucic, D.,Deshayes, K.,Fairbrother, W.J. (deposition date: 2003-04-03, release date: 2003-08-26, Last modification date: 2024-02-14)

Primary citation

Franklin, M.C.,Kadkhodayan, S.,Ackerly, H.,Alexandru, D.,Distefano, M.D.,Elliott, L.O.,Flygare, J.A.,Mausisa, G.,Okawa, D.C.,Ong, D.,Vucic, D.,Deshayes, K.,Fairbrother, W.J.
Structure and Function Analysis of Peptide Antagonists of Melanoma Inhibitor of Apoptosis (ML-IAP)
Biochemistry, 42:8223-8231, 2003

PubMed Abstract: 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.

PubMed: 12846571
DOI: 10.1021/bi034227t

Experimental method

X-RAY DIFFRACTION (2.2 Å)