4IJW

Crystal structure of 11b-HSD1 double mutant (L262R, F278E) in complex with 3-[1-(4-chlorophenyl)cyclopropyl]-8-cyclopropyl[1,2,4]triazolo[4,3-a]pyridine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.205 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11 beta-Hydroxysteroid Dehydrogenase Type 1 (11 beta-HSD-1).

Li, J.Kennedy, L.J.Wang, H.Li, J.J.Walker, S.J.Hong, Z.O'Connor, S.P.Nayeem, A.Camac, D.M.Morin, P.E.Sheriff, S.Wang, M.Harper, T.Golla, R.Seethala, R.Harrity, T.Ponticiello, R.P.Morgan, N.N.Taylor, J.R.Zebo, R.Gordon, D.A.Robl, J.A.

(2014) Bioorg Med Chem Lett 5: 803-808

  • DOI: https://doi.org/10.1021/ml500144h
  • Primary Citation of Related Structures:  
    4IJU, 4IJV, 4IJW

  • PubMed Abstract: 

    Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Department of Biology, Lead Evaluation, CADD, Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb , Bldg 13, Princeton, New Jersey 08543-5400, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Corticosteroid 11-beta-dehydrogenase isozyme 1A,
B,
C [auth D],
D [auth E]
286Homo sapiensMutation(s): 2 
Gene Names: HSD11B1HSD11HSD11L
EC: 1.1.1.146
UniProt & NIH Common Fund Data Resources
Find proteins for P28845 (Homo sapiens)
Explore P28845 
Go to UniProtKB:  P28845
PHAROS:  P28845
GTEx:  ENSG00000117594 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28845
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
1EQ BindingDB:  4IJW IC50: min: 1.6, max: 13 (nM) from 2 assay(s)
Binding MOAD:  4IJW IC50: 1.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.205 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.5α = 90
b = 94.3β = 90
c = 167.4γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2014-06-11 
  • Deposition Author(s): Sheriff, S.

Revision History  (Full details and data files)

  • Version 1.0: 2014-06-11
    Type: Initial release
  • Version 1.1: 2014-08-06
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations