4EFU

Hsp90 Alpha N-terminal Domain in Complex with an Inhibitor 6-Hydroxy-3-(3-methyl-benzyl)-1H-indazole-5-carboxylic acid benzyl-methyl-amide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90

Buchstaller, H.-P.Eggenweiler, H.-M.Sirrenberg, C.Graedler, U.Musil, D.Hoppe, E.Zimmermann, A.Schwartz, H.Maerz, J.Bomke, J.Wegener, A.Wolf, M.

(2012) Bioorg Med Chem Lett 22: 4396-4403

  • DOI: https://doi.org/10.1016/j.bmcl.2012.04.121
  • Primary Citation of Related Structures:  
    4EEH, 4EFT, 4EFU

  • PubMed Abstract: 

    Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines.


  • Organizational Affiliation

    Merck Serono Research, Merck KGaA, Frankfurter Straße 250, D-64293 Darmstadt, Germany. hans-peter.buchstaller@merckgroup.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein HSP 90-alpha229Homo sapiensMutation(s): 0 
Gene Names: HSP90A
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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EFU
Query on EFU

Download Ideal Coordinates CCD File 
B [auth A]N-benzyl-6-hydroxy-N-methyl-3-(3-methylbenzyl)-1H-indazole-5-carboxamide
C24 H23 N3 O2
JTCGRDMMRLTULM-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
EFU Binding MOAD:  4EFU IC50: 250 (nM) from 1 assay(s)
PDBBind:  4EFU IC50: 250 (nM) from 1 assay(s)
BindingDB:  4EFU IC50: 250 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.205 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.588α = 90
b = 90.623β = 90
c = 98.788γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
MOLREPphasing
BUSTERrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-06-27
    Type: Initial release