4AWJ

pVHL:EloB:EloC complex, in complex with capped Hydroxyproline


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

Dissecting Fragment-Based Lead Discovery at the Von Hippel-Lindau Protein:Hypoxia Inducible Factor 1Alpha Protein-Protein Interface.

Van Molle, I.Thomann, A.Buckley, D.L.So, E.C.Lang, S.Crews, C.M.Ciulli, A.

(2012) Chem Biol 19: 1300

  • DOI: https://doi.org/10.1016/j.chembiol.2012.08.015
  • Primary Citation of Related Structures:  
    3ZTC, 3ZTD, 4AJY, 4AWJ

  • PubMed Abstract: 

    Fragment screening is widely used to identify attractive starting points for drug design. However, its potential and limitations to assess the tractability of often challenging protein:protein interfaces have been underexplored. Here, we address this question by means of a systematic deconstruction of lead-like inhibitors of the pVHL:HIF-1α interaction into their component fragments. Using biophysical techniques commonly employed for screening, we could only detect binding of fragments that violate the Rule of Three, are more complex than those typically screened against classical druggable targets, and occupy two adjacent binding subsites at the interface rather than just one. Analyses based on ligand and group lipophilicity efficiency of anchored fragments were applied to dissect the individual subsites and probe for binding hot spots. The implications of our findings for targeting protein interfaces by fragment-based approaches are discussed.


  • Organizational Affiliation

    Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 2
A, D, G, J
104Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15370 (Homo sapiens)
Explore Q15370 
Go to UniProtKB:  Q15370
PHAROS:  Q15370
GTEx:  ENSG00000103363 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15370
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 1
B, E, H, K
97Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15369 (Homo sapiens)
Explore Q15369 
Go to UniProtKB:  Q15369
PHAROS:  Q15369
GTEx:  ENSG00000154582 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15369
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
VON HIPPEL-LINDAU DISEASE TUMOR SUPPRESSOR
C, F, I, L
163Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P40337 (Homo sapiens)
Explore P40337 
Go to UniProtKB:  P40337
PHAROS:  P40337
GTEx:  ENSG00000134086 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP40337
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
V6F
Query on V6F

Download Ideal Coordinates CCD File 
O [auth C],
Q [auth F],
T [auth I],
W [auth L]
(4R)-1-acetyl-4-hydroxy-N-methyl-L-prolinamide
C8 H14 N2 O3
XAZYBLFYZNUKHD-RQJHMYQMSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
V [auth J]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACY
Query on ACY

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R [auth F]ACETIC ACID
C2 H4 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
M [auth A]
N [auth B]
P [auth C]
S [auth F]
U [auth I]
M [auth A],
N [auth B],
P [auth C],
S [auth F],
U [auth I],
X [auth L]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CAS
Query on CAS
A, D, G, J
L-PEPTIDE LINKINGC5 H12 As N O2 SCYS
Binding Affinity Annotations 
IDSourceBinding Affinity
V6F PDBBind:  4AWJ Kd: 1.00e+7 (nM) from 1 assay(s)
Binding MOAD:  4AWJ Kd: 1.00e+7 (nM) from 1 assay(s)
BindingDB:  4AWJ Kd: min: 4.90e+6, max: 1.00e+7 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 
  • Space Group: P 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.4α = 90
b = 93.4β = 90
c = 362.04γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-14
    Type: Initial release