1OY7

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.152 
  • R-Value Observed: 0.155 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

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

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.

(2003) Biochemistry 42: 8223-8231

  • DOI: https://doi.org/10.1021/bi034227t
  • Primary Citation of Related Structures:  
    1OXN, 1OXQ, 1OY7

  • 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.


  • Organizational Affiliation

    Department of Protein Engineering, Genentech, Inc., One DNA Way, South San Francisco, California 94080, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Baculoviral IAP repeat-containing protein 7
A, B, C, D, E
140Homo sapiensMutation(s): 0 
Gene Names: BIRC7 OR KIAP OR MLIAP OR LIVIN
UniProt & NIH Common Fund Data Resources
Find proteins for Q96CA5 (Homo sapiens)
Explore Q96CA5 
Go to UniProtKB:  Q96CA5
PHAROS:  Q96CA5
GTEx:  ENSG00000101197 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ96CA5
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
AEVVAVKSE peptide9N/AMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.152 
  • R-Value Observed: 0.155 
  • Space Group: P 32
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.878α = 90
b = 83.878β = 90
c = 94.34γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2003-08-26
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.3: 2023-08-16
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary