4BPK

Bcl-xL bound to alpha beta Puma BH3 peptide 5


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.221 

wwPDB Validation   3D Report Full Report


This is version 4.1 of the entry. See complete history


Literature

Structure-Guided Rational Design of Alpha/Beta-Peptide Foldamers with High Affinity for Bcl-2 Family Prosurvival Proteins.

Smith, B.J.Lee, E.F.Checco, J.W.Evangelista, M.Gellman, S.H.Fairlie, W.D.

(2013) Chembiochem 14: 1564

  • DOI: https://doi.org/10.1002/cbic.201300351
  • Primary Citation of Related Structures:  
    4BPI, 4BPJ, 4BPK

  • PubMed Abstract: 

    We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported α/β-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal structure of the Puma-derived α/β-peptide complexed to Bcl-x(L) was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three α residues of the original α/β backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-x(L). Crystal structures of a number of the new α/β-peptides bound to either Mcl-1 or Bcl-x(L) validated the selection of each substitution. Overall, our findings demonstrate that structure-guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners.


  • Organizational Affiliation

    Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria (Australia). brian.smith@latrobe.edu.au.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BCL-2-LIKE PROTEIN 1
A, B
157Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q07817 (Homo sapiens)
Explore Q07817 
Go to UniProtKB:  Q07817
PHAROS:  Q07817
GTEx:  ENSG00000171552 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07817
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
ALPHA BETA BH3-PEPTIDE
C, D
22Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9BXH1 (Homo sapiens)
Explore Q9BXH1 
Go to UniProtKB:  Q9BXH1
PHAROS:  Q9BXH1
GTEx:  ENSG00000105327 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9BXH1
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CD
Query on CD

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
L [auth B],
M [auth B],
N [auth B],
O [auth B],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
T [auth B]
CADMIUM ION
Cd
WLZRMCYVCSSEQC-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
K [auth A],
U [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Modified Residues  6 Unique
IDChains TypeFormula2D DiagramParent
AHP
Query on AHP
C, D
L-PEPTIDE LINKINGC7 H15 N O2ALA
B3A
Query on B3A
C, D
L-PEPTIDE LINKINGC4 H9 N O2ALA
B3D
Query on B3D
C, D
PEPTIDE-LIKEC5 H9 N O4ASP
B3E
Query on B3E
C, D
L-PEPTIDE LINKINGC6 H11 N O4GLU
HR7
Query on HR7
C, D
L-PEPTIDE LINKINGC7 H16 N4 O2ARG
HT7
Query on HT7
C, D
L-PEPTIDE LINKINGC12 H14 N2 O2TRP
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.221 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.175α = 90
b = 72.133β = 90
c = 80.579γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-04-09
    Type: Initial release
  • Version 1.1: 2017-05-10
    Changes: Data collection
  • Version 2.0: 2018-06-20
    Changes: Atomic model, Data collection, Derived calculations
  • Version 3.0: 2019-04-24
    Changes: Data collection, Polymer sequence
  • Version 3.1: 2019-07-10
    Changes: Data collection
  • Version 4.0: 2023-11-15
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Other
  • Version 4.1: 2023-12-20
    Changes: Refinement description