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PDBsum entry 3ook

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protein ligands Protein-protein interface(s) links
Hormone receptor PDB id
3ook
Jmol PyMol
Contents
Protein chains
230 a.a. *
12 a.a. *
11 a.a. *
Ligands
OOK ×2
Waters ×166
* Residue conservation analysis
PDB id:
3ook
Name: Hormone receptor
Title: Crystal structure of human fxr in complex with 4-({(2s)-2-[2 chlorophenyl)-5,6-difluoro-1h-benzimidazol-1-yl]-2- cyclohexylacetyl}amino)-3,5-difluorobenzoic acid
Structure: Bile acid receptor. Chain: a, c. Fragment: unp residues 258-486. Synonym: fxr, farnesoid x-activated receptor, farnesol rece 1, nuclear receptor subfamily 1 group h member 4, retinoid receptor-interacting protein 14, rxr-interacting protein 14 engineered: yes. Mutation: yes. Peptide of nuclear receptor coactivator 1.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: nr1h4, hcg_20893. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: this sequence occurs naturally in humans
Resolution:
2.29Å     R-factor:   0.231     R-free:   0.271
Authors: M.G.Rudolph
Key ref: H.G.Richter et al. (2011). Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties. Bioorg Med Chem Lett, 21, 1134-1140. PubMed id: 21269824
Date:
31-Aug-10     Release date:   19-Jan-11    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q96RI1  (NR1H4_HUMAN) -  Bile acid receptor
Seq:
Struc:
486 a.a.
230 a.a.*
Protein chain
Pfam   ArchSchema ?
Q15788  (NCOA1_HUMAN) -  Nuclear receptor coactivator 1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1441 a.a.
12 a.a.
Protein chain
Pfam   ArchSchema ?
Q15788  (NCOA1_HUMAN) -  Nuclear receptor coactivator 1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1441 a.a.
11 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains B, D: E.C.2.3.1.48  - Histone acetyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetyl-CoA + [histone] = CoA + acetyl-[histone]
Acetyl-CoA
+ [histone]
= CoA
+ acetyl-[histone]
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 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  

 

 
    Added reference    
 
 
Bioorg Med Chem Lett 21:1134-1140 (2011)
PubMed id: 21269824  
 
 
Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties.
H.G.Richter, G.M.Benson, K.H.Bleicher, D.Blum, E.Chaput, N.Clemann, S.Feng, C.Gardes, U.Grether, P.Hartman, B.Kuhn, R.E.Martin, J.M.Plancher, M.G.Rudolph, F.Schuler, S.Taylor.
 
  ABSTRACT  
 
Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.
 

 

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