2IWS

Radicicol analogues bound to the ATP site of HSP90


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.223 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Inhibition of Hsp90 with Synthetic Macrolactones: Synthesis and Structural and Biological Evaluation of Ring and Conformational Analogs of Radicicol.

Proisy, N.Sharp, S.Y.Boxall, K.Connelly, S.Roe, S.M.Prodromou, C.Slawin, A.M.Z.Pearl, L.H.Workman, P.Moody, C.J.

(2006) Chem Biol 13: 1203

  • DOI: https://doi.org/10.1016/j.chembiol.2006.09.015
  • Primary Citation of Related Structures:  
    2CGF, 2IWS, 2IWU, 2IWX

  • PubMed Abstract: 

    A series of benzo-macrolactones of varying ring size and conformation has been prepared by chemical synthesis and evaluated by structural and biological techniques. Thus, 12- to 16-membered lactones were obtained by concise routes, involving ring-closing metathesis as a key step. In enzyme assays, the 13-, 15-, and 16-membered analogs are good inhibitors, suggesting that they can adopt the required conformation to fit in the ATP-binding site. This was confirmed by cocrystallization of 13-, 14-, and 15-membered lactones with the N-terminal domain of yeast Hsp90, showing that they bind similarly to the "natural" 14-membered radicicol. The most active compounds in the ATPase assays also showed the greatest growth-inhibitory potency in HCT116 human colon cancer cells and the established molecular signature of Hsp90 inhibition, i.e., depletion of client proteins with upregulation of Hsp70.


  • Organizational Affiliation

    School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ATP-DEPENDENT MOLECULAR CHAPERONE HSP82214Saccharomyces cerevisiaeMutation(s): 0 
UniProt
Find proteins for P02829 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P02829 
Go to UniProtKB:  P02829
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP02829
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NP4
Query on NP4

Download Ideal Coordinates CCD File 
B [auth A](5Z)-12-CHLORO-13,15-DIHYDROXY-4,7,8,9-TETRAHYDRO-2-BENZOXACYCLOTRIDECINE-1,10(3H,11H)-DIONE
C16 H17 Cl O5
AQKZYZQONWDDLS-IWQZZHSRSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
NP4 PDBBind:  2IWS Kd: 440 (nM) from 1 assay(s)
BindingDB:  2IWS IC50: min: 500, max: 2400 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.223 
  • Space Group: P 43 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.841α = 90
b = 73.841β = 90
c = 109.135γ = 90
Software Package:
Software NamePurpose
CNSrefinement
MOSFLMdata reduction
SCALAdata 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: 2006-11-30
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-05-22
    Changes: Data collection, Other, Refinement description
  • Version 1.4: 2023-12-13
    Changes: Data collection, Database references, Other, Refinement description