4NH7

Correlation between chemotype-dependent binding conformations of HSP90 alpha/beta and isoform selectivity


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Correlation between chemotype-dependent binding conformations of HSP90 alpha / beta and isoform selectivity-Implications for the structure-based design of HSP90 alpha / beta selective inhibitors for treating neurodegenerative diseases.

Ernst, J.T.Liu, M.Zuccola, H.Neubert, T.Beaumont, K.Turnbull, A.Kallel, A.Vought, B.Stamos, D.

(2014) Bioorg Med Chem Lett 24: 204-208

  • DOI: https://doi.org/10.1016/j.bmcl.2013.11.036
  • Primary Citation of Related Structures:  
    4NH7, 4NH8, 4NH9

  • PubMed Abstract: 

    HSP90 continues to be a target of interest for neurodegeneration indications. Selective knockdown of the HSP90 cytosolic isoforms α and β is sufficient to reduce mutant huntingtin protein levels in vitro. Chemotype-dependent binding conformations of HSP90α/β appear to strongly influence isoform selectivity. The rational design of HSP90α/β inhibitors selective versus the mitochondrial (TRAP1) and endoplasmic reticulum (GRP94) isoforms offers a potential mitigating strategy for mechanism-based toxicities. Better tolerated HSP90 inhibitors would be attractive for targeting chronic neurodegenerative diseases such as Huntington's disease.


  • Organizational Affiliation

    Vertex Pharmaceuticals, Department of Chemistry and Drug Innovation, 11010 Torreyana Road, San Diego, CA 92121, United States. Electronic address: Justin_Ernst@vrtx.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein HSP 90-alpha
A, B
233Homo sapiensMutation(s): 0 
Gene Names: HSP90AA1HSP90AHSPC1HSPCA
UniProt & NIH Common Fund Data Resources
Find proteins for P07900 (Homo sapiens)
Explore P07900 
Go to UniProtKB:  P07900
PHAROS:  P07900
GTEx:  ENSG00000080824 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07900
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
E0G Binding MOAD:  4NH7 Ki: 4 (nM) from 1 assay(s)
BindingDB:  4NH7 Kd: 4 (nM) from 1 assay(s)
IC50: min: 1, max: 1.00e+4 (nM) from 7 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 114.98α = 90
b = 88.04β = 124.53
c = 71.07γ = 90
Software Package:
Software NamePurpose
PROCESSdata collection
BUSTERrefinement
PROCESSdata reduction
PROCESSdata scaling
BUSTERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-01-15
    Type: Initial release
  • Version 2.0: 2017-11-29
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Source and taxonomy, Structure summary
  • Version 2.1: 2024-02-28
    Changes: Data collection, Database references, Derived calculations