5LLI

pVHL:EloB:EloC in complex with VH298


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.199 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Potent and selective chemical probe of hypoxic signalling downstream of HIF-alpha hydroxylation via VHL inhibition.

Frost, J.Galdeano, C.Soares, P.Gadd, M.S.Grzes, K.M.Ellis, L.Epemolu, O.Shimamura, S.Bantscheff, M.Grandi, P.Read, K.D.Cantrell, D.A.Rocha, S.Ciulli, A.

(2016) Nat Commun 7: 13312-13312

  • DOI: https://doi.org/10.1038/ncomms13312
  • Primary Citation of Related Structures:  
    5LLI

  • PubMed Abstract: 

    Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.


  • Organizational Affiliation

    Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Transcription elongation factor B polypeptide 2
A, D, G, J
104Homo sapiensMutation(s): 0 
Gene Names: TCEB2
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
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Transcription elongation factor B polypeptide 1
B, E, H, K
97Homo sapiensMutation(s): 0 
Gene Names: TCEB1
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
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Von Hippel-Lindau disease tumor suppressor
C, F, I, L
162Homo sapiensMutation(s): 0 
Gene Names: VHL
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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6Z3
Query on 6Z3

Download Ideal Coordinates CCD File 
M [auth C],
N [auth F],
O [auth I],
P [auth L]
(2~{S},4~{R})-1-[(2~{S})-2-[(1-cyanocyclopropyl)carbonylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide
C27 H33 N5 O4 S
NDVQUNZCNAMROD-RZUBCFFCSA-N
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
6Z3 Binding MOAD:  5LLI Kd: 90 (nM) from 1 assay(s)
BindingDB:  5LLI Kd: min: 52, max: 99 (nM) from 6 assay(s)
IC50: 88 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.199 
  • Space Group: P 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.643α = 90
b = 94.643β = 90
c = 368.582γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Research CouncilUnited KingdomERC-2012-StG-311460

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-09
    Type: Initial release
  • Version 1.1: 2016-11-16
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Refinement description