3OLF

Crystal structure of human FXR in complex with 4-({(2S)-2-[2-(4-chlorophenyl)-5,6-difluoro-1H-benzimidazol-1-yl]-2-cyclohexylacetyl}amino)-3-methylbenzoic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties

Richter, H.G.F.Benson, G.M.Bleicher, K.H.Blum, D.Chaput, E.Clemann, N.Feng, S.Gardes, C.Grether, U.Hartman, P.Kuhn, B.Martin, R.E.Plancher, J.M.Rudolph, M.G.Schuler, F.Taylor, S.

(2011) Bioorg Med Chem Lett 21: 1134-1140

  • DOI: https://doi.org/10.1016/j.bmcl.2010.12.123
  • Primary Citation of Related Structures:  
    3OLF, 3OMK, 3OMM, 3OOF, 3OOK

  • PubMed 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.


  • Organizational Affiliation

    F. Hoffmann-La Roche Ltd, Pharmaceutical Research, Grenzacherstrasse, CH-4070 Basel, Switzerland. hans.richter@roche.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bile acid receptor
A, C
233Homo sapiensMutation(s): 2 
Gene Names: NR1H4HCG_20893
UniProt & NIH Common Fund Data Resources
Find proteins for Q96RI1 (Homo sapiens)
Explore Q96RI1 
Go to UniProtKB:  Q96RI1
PHAROS:  Q96RI1
GTEx:  ENSG00000012504 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ96RI1
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
peptide of Nuclear receptor coactivator 1
B, D
14N/AMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15788 (Homo sapiens)
Explore Q15788 
Go to UniProtKB:  Q15788
PHAROS:  Q15788
GTEx:  ENSG00000084676 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15788
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
OLF
Query on OLF

Download Ideal Coordinates CCD File 
E [auth A],
F [auth C]
4-({(2S)-2-[2-(4-chlorophenyl)-5,6-difluoro-1H-benzimidazol-1-yl]-2-cyclohexylacetyl}amino)-3-methylbenzoic acid
C29 H26 Cl F2 N3 O3
XAVJTYOBWCSWFJ-SANMLTNESA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
OLF PDBBind:  3OLF IC50: 20 (nM) from 1 assay(s)
BindingDB:  3OLF IC50: 20 (nM) from 1 assay(s)
EC50: 500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.28α = 90
b = 84.86β = 90
c = 191.56γ = 90
Software Package:
Software NamePurpose
PHASERphasing
BUSTERrefinement
HKL-2000data reduction
SADABSdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-01-19
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2014-02-26
    Changes: Database references
  • Version 1.3: 2024-03-20
    Changes: Data collection, Database references, Derived calculations