spacer
spacer

PDBsum entry 3k23

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Transcription PDB id
3k23
Jmol
Contents
Protein chains
245 a.a. *
247 a.a. *
246 a.a. *
Ligands
ALA-LEU-LEU-ARG-
TYR-LEU-LEU-ASP-
LYS
ASN-ALA-LEU-LEU-
ARG-TYR-LEU-LEU-
ASP-LYS
GLU-ASN-ALA-LEU-
LEU-ARG-TYR-LEU-
LEU-ASP
JZN ×3
Waters ×47
* Residue conservation analysis
PDB id:
3k23
Name: Transcription
Title: Glucocorticoid receptor with bound d-prolinamide 11
Structure: Glucocorticoid receptor. Chain: a, b, c. Fragment: unp residues 521-777, ligand binding domain. Synonym: gr, nuclear receptor subfamily 3 group c member 1. Engineered: yes. Mutation: yes. Nuclear receptor coactivator 2. Chain: d, e, f. Fragment: unp residues 740-751.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: grl, nr3c1. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes
Resolution:
3.00Å     R-factor:   0.229     R-free:   0.289
Authors: K.B.Biggadike,I.M.Mclay,K.P.Madauss,S.P.Williams,R.K.Bledsoe
Key ref:
K.Biggadike et al. (2009). Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor. Proc Natl Acad Sci U S A, 106, 18114-18119. PubMed id: 19822747 DOI: 10.1073/pnas.0909125106
Date:
29-Sep-09     Release date:   27-Oct-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P04150  (GCR_HUMAN) -  Glucocorticoid receptor
Seq:
Struc:
 
Seq:
Struc:
777 a.a.
245 a.a.*
Protein chain
Pfam   ArchSchema ?
P04150  (GCR_HUMAN) -  Glucocorticoid receptor
Seq:
Struc:
 
Seq:
Struc:
777 a.a.
247 a.a.*
Protein chain
Pfam   ArchSchema ?
P04150  (GCR_HUMAN) -  Glucocorticoid receptor
Seq:
Struc:
 
Seq:
Struc:
777 a.a.
246 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     DNA binding     3 terms  

 

 
DOI no: 10.1073/pnas.0909125106 Proc Natl Acad Sci U S A 106:18114-18119 (2009)
PubMed id: 19822747  
 
 
Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor.
K.Biggadike, R.K.Bledsoe, D.M.Coe, T.W.Cooper, D.House, M.A.Iannone, S.J.Macdonald, K.P.Madauss, I.M.McLay, T.J.Shipley, S.J.Taylor, T.B.Tran, I.J.Uings, V.Weller, S.P.Williams.
 
  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.
 
  Selected figure(s)  
 
Figure 1.
(A) Fluticasone furoate–GR LBD crystal structure; (B) deacetylcortivazol–GR LBD crystal structure; (C) indazole 6–GR model showing access to “meta” channel; (D) AlleGrow alaninamide 10, showing growth into “meta” channel.
Figure 2.
(A) D-prolinamide 11 GR LBD crystal structure; (B) truncated D-alaninamide 13 GR LBD crystal structure, showing at bottom left the tail of β-hexylglucoside pushing into unoccupied portions of the 17α pocket.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20398732 A.E.Coutinho, and K.E.Chapman (2011).
The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.
  Mol Cell Endocrinol, 335, 2.  
21318203 M.Awais, and T.Ozawa (2011).
Illuminating intracellular signaling and molecules for single cell analysis.
  Mol Biosyst, 7, 1376-1387.  
20333619 A.S.Veleiro, L.D.Alvarez, S.L.Eduardo, and G.Burton (2010).
Structure of the glucocorticoid receptor, a flexible protein that can adapt to different ligands.
  ChemMedChem, 5, 649-659.  
20600811 K.De Bosscher, I.M.Beck, and G.Haegeman (2010).
Classic glucocorticoids versus non-steroidal glucocorticoid receptor modulators: survival of the fittest regulator of the immune system?
  Brain Behav Immun, 24, 1035-1042.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.