6ASQ | pdb_00006asq

Structure of Grp94 bound to methyl 2-[2-(2-benzylpyridin-3-yl)ethyl]-3-chloro-4,6-dihydroxybenzoate, a pan-Hsp90 inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 
    0.237 (Depositor), 0.240 (DCC) 
  • R-Value Work: 
    0.197 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 
    0.200 (Depositor) 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted VC4Click on this verticalbar to view details

This is version 1.3 of the entry. See complete history


Literature

Trifunctional High-Throughput Screen Identifies Promising Scaffold To Inhibit Grp94 and Treat Myocilin-Associated Glaucoma.

Huard, D.J.E.Crowley, V.M.Du, Y.Cordova, R.A.Sun, Z.Tomlin, M.O.Dickey, C.A.Koren, J.Blair, L.Fu, H.Blagg, B.S.J.Lieberman, R.L.

(2018) ACS Chem Biol 13: 933-941

  • DOI: https://doi.org/10.1021/acschembio.7b01083
  • Primary Citation of Related Structures:  
    6ASP, 6ASQ

  • PubMed Abstract: 

    Gain-of-function mutations within the olfactomedin (OLF) domain of myocilin result in its toxic intracellular accumulation and hasten the onset of open-angle glaucoma. The absence of myocilin does not cause disease; therefore, strategies aimed at eliminating myocilin could lead to a successful glaucoma treatment. The endoplasmic reticulum Hsp90 paralog Grp94 accelerates OLF aggregation. Knockdown or pharmacological inhibition of Grp94 in cells facilitates clearance of mutant myocilin via a non-proteasomal pathway. Here, we expanded our support for targeting Grp94 over cytosolic paralogs Hsp90α and Hsp90β. We then developed a high-throughput screening assay to identify new chemical matter capable of disrupting the Grp94/OLF interaction. When applied to a blind, focused library of 17 Hsp90 inhibitors, our miniaturized single-read in vitro thioflavin T -based kinetics aggregation assay exclusively identified compounds that target the chaperone N-terminal nucleotide binding site. In follow up studies, one compound (2) decreased the extent of co-aggregation of Grp94 with OLF in a dose-dependent manner in vitro, and enabled clearance of the aggregation-prone full-length myocilin variant I477N in cells without inducing the heat shock response or causing cytotoxicity. Comparison of the co-crystal structure of compound 2 and another non-selective hit in complex with the N-terminal domain of Grp94 reveals a docking mode tailored to Grp94 and explains its selectivity. A new lead compound has been identified, supporting a targeted chemical biology assay approach to develop a protein degradation-based therapy for myocilin-associated glaucoma by selectively inhibiting Grp94.


  • Organizational Affiliation

    School of Chemistry & Biochemistry , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Endoplasmin
A, B
233Canis lupus familiarisMutation(s): 0 
Gene Names: HSP90B1GRP94TRA1
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
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
VC4 (Subject of Investigation/LOI)
Query on VC4

Download Ideal Coordinates CCD File 
N [auth A],
X [auth B]
methyl 2-[2-(2-benzylpyridin-3-yl)ethyl]-3-chloro-4,6-dihydroxybenzoate
C22 H20 Cl N O4
XODLEZWUEQKVLO-UHFFFAOYSA-N
PE8
Query on PE8

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
F [auth A]
G [auth A]
3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL
C16 H34 O9
GLZWNFNQMJAZGY-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
U [auth B]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
L [auth A],
M [auth A],
V [auth B],
W [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free:  0.237 (Depositor), 0.240 (DCC) 
  • R-Value Work:  0.197 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 0.200 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.431α = 90
b = 84.717β = 90
c = 95.759γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted VC4Click on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-04-18
    Type: Initial release
  • Version 1.1: 2018-05-02
    Changes: Data collection, Database references
  • Version 1.2: 2019-04-17
    Changes: Author supporting evidence, Data collection
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description