3K22

Glucocorticoid Receptor with Bound alaninamide 10 with TIF2 peptide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.214 

wwPDB Validation   3D Report Full Report


This is version 1.7 of the entry. See complete history


Literature

Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor.

Biggadike, K.Bledsoe, R.K.Coe, D.M.Cooper, T.W.House, D.Iannone, M.A.Macdonald, S.J.Madauss, K.P.McLay, I.M.Shipley, T.J.Taylor, S.J.Tran, T.B.Uings, I.J.Weller, V.Williams, S.P.

(2009) Proc Natl Acad Sci U S A 106: 18114-18119

  • DOI: https://doi.org/10.1073/pnas.0909125106
  • Primary Citation of Related Structures:  
    3K22, 3K23

  • PubMed Abstract: 

    Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14. Data with the pyrrolidinone amide 12 demonstrate the potential for further elaboration within the "meta" channel to deliver compounds with selectivity for the desired transrepressive activity of glucocorticoids. The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators.


  • Organizational Affiliation

    Medicinal Chemistry, Respiratory Center of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Center, Stevenage, Hertfordshire SG1 2NY, United Kingdom. keith.b.biggadike@gsk.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glucocorticoid receptorA,
C [auth B]
259Homo sapiensMutation(s): 2 
Gene Names: GRLNR3C1PGR
UniProt & NIH Common Fund Data Resources
Find proteins for P04150 (Homo sapiens)
Explore P04150 
Go to UniProtKB:  P04150
PHAROS:  P04150
GTEx:  ENSG00000113580 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04150
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Transcriptional Intermediary Factor 2B [auth H],
D
12N/AMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15596 (Homo sapiens)
Explore Q15596 
Go to UniProtKB:  Q15596
PHAROS:  Q15596
GTEx:  ENSG00000140396 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15596
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
JZS PDBBind:  3K22 IC50: 12.59 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.214 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 127.597α = 90
b = 127.597β = 90
c = 78.23γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-08-11
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2013-09-25
    Changes: Derived calculations
  • Version 1.3: 2017-11-01
    Changes: Refinement description
  • Version 1.4: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Data collection, Database references, Derived calculations
  • Version 1.5: 2021-10-13
    Changes: Database references, Structure summary
  • Version 1.6: 2024-02-21
    Changes: Data collection
  • Version 1.7: 2024-03-13
    Changes: Source and taxonomy, Structure summary