2GFD

GRP94 in complex with the novel HSP90 Inhibitor Radamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.211 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Different poses for ligand and chaperone in inhibitor-bound Hsp90 and GRP94: implications for paralog-specific drug design.

Immormino, R.M.Metzger, L.E.Reardon, P.N.Dollins, D.E.Blagg, B.S.Gewirth, D.T.

(2009) J Mol Biol 388: 1033-1042

  • DOI: https://doi.org/10.1016/j.jmb.2009.03.071
  • Primary Citation of Related Structures:  
    2EXL, 2FXS, 2GFD

  • PubMed Abstract: 

    Hsp90 chaperones contain an N-terminal ATP binding site that has been effectively targeted by competitive inhibitors. Despite the myriad of inhibitors, none to date have been designed to bind specifically to just one of the four mammalian Hsp90 paralogs, which are cytoplasmic Hsp90alpha and beta, endoplasmic reticulum GRP94, and mitochondrial Trap-1. Given that each of the Hsp90 paralogs is responsible for chaperoning a distinct set of client proteins, specific targeting of one Hsp90 paralog may result in higher efficacy and therapeutic control. Specific inhibitors may also help elucidate the biochemical roles of each Hsp90 paralog. Here, we present side-by-side comparisons of the structures of yeast Hsp90 and mammalian GRP94, bound to the pan-Hsp90 inhibitors geldanamycin (Gdm) and radamide. These structures reveal paralog-specific differences in the Hsp90 and GRP94 conformations in response to Gdm binding. We also report significant variation in the pose and disparate binding affinities for the Gdm-radicicol chimera radamide when bound to the two paralogs, which may be exploited in the design of paralog-specific inhibitors.


  • Organizational Affiliation

    Hauptman-Woodward Medical Research Institute, Buffalo, NY 14203, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Endoplasmin
A, B
236Canis lupus familiarisMutation(s): 0 
Gene Names: TRA1
UniProt
Find proteins for P41148 (Canis lupus familiaris)
Explore P41148 
Go to UniProtKB:  P41148
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP41148
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
RDA Binding MOAD:  2GFD Kd: 520 (nM) from 1 assay(s)
PDBBind:  2GFD Kd: 520 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.211 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.49α = 90
b = 84.57β = 90
c = 95.58γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data reduction
XDSdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-04-03
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-08-02
    Changes: Source and taxonomy
  • Version 1.4: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description