5NVX

pVHL:EloB:EloC in complex with (2S,4R)-1-((S)-2-(1-fluorocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (ligand 10)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298).

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

(2018) J Med Chem 61: 599-618

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00675
  • Primary Citation of Related Structures:  
    5NVV, 5NVW, 5NVX, 5NVY, 5NVZ, 5NW0, 5NW1, 5NW2

  • PubMed Abstract: 

    The von Hippel-Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways and new VHL ligands for next-generation PROTACs.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Elongin-B
A, D, G, J
104Homo sapiensMutation(s): 0 
Gene Names: ELOBTCEB2
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
Elongin-C
B, E, H, K
97Homo sapiensMutation(s): 0 
Gene Names: ELOCTCEB1
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
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
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  • Reference Sequence
Small Molecules
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
4YY BindingDB:  5NVX Kd: min: 16, max: 90 (nM) from 4 assay(s)
Binding MOAD:  5NVX Kd: 44 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 
  • Space Group: P 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.445α = 90
b = 93.445β = 90
c = 365.195γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Research CouncilERC-2012-StG-311460 DrugE3CRLs

Revision History  (Full details and data files)

  • Version 1.0: 2017-09-20
    Type: Initial release
  • Version 1.1: 2018-02-07
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description