2XDK

Structure of HSP90 with small molecule inhibitor bound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency.

Murray, C.W.Carr, M.G.Callaghan, O.Chessari, G.Congreve, M.Cowan, S.Coyle, J.E.Downham, R.Figueroa, E.Frederickson, M.Graham, B.Mcmenamin, R.O'Brien, M.A.Patel, S.Phillips, T.R.Williams, G.Woodhead, A.J.Woolford, A.J.A.

(2010) J Med Chem 53: 5942

  • DOI: https://doi.org/10.1021/jm100059d
  • Primary Citation of Related Structures:  
    2XDK, 2XDL, 2XDS, 2XDU, 2XDX, 2XHR, 2XHT, 2XHX, 2XK2

  • PubMed Abstract: 

    Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer.


  • Organizational Affiliation

    Astex Therapeutics, Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK. c.murray@astex-therapeutics.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HEAT SHOCK PROTEIN HSP 90-ALPHA249Homo sapiensMutation(s): 0 
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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
XDK
Query on XDK

Download Ideal Coordinates CCD File 
B [auth A]2-AMINO-4-PYRIDYL-PYRIMIDINE
C9 H8 N4
LQHQKYWYKPLKCH-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
XDK BindingDB:  2XDK Kd: 2.50e+5 (nM) from 1 assay(s)
Binding MOAD:  2XDK Kd: 2.50e+5 (nM) from 1 assay(s)
PDBBind:  2XDK Kd: 2.50e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.175 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.591α = 90
b = 44.211β = 115.89
c = 54.298γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2010-09-01
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance