3O57

Catalytic domain of human phosphodiesterase 4b2b in complex with a 5-heterocycle pyrazolopyridine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.

Mitchell, C.J.Ballantine, S.P.Coe, D.M.Cook, C.M.Delves, C.J.Dowle, M.D.Edlin, C.D.Hamblin, J.N.Holman, S.Johnson, M.R.Jones, P.S.Keeling, S.E.Kranz, M.Lindvall, M.Lucas, F.S.Neu, M.Solanke, Y.E.Somers, D.O.Trivedi, N.A.Wiseman, J.O.

(2010) Bioorg Med Chem Lett 20: 5803-5806

  • DOI: https://doi.org/10.1016/j.bmcl.2010.07.136
  • Primary Citation of Related Structures:  
    3O56, 3O57

  • PubMed Abstract: 

    Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.


  • Organizational Affiliation

    GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. charlotte.j.mitchell@gsk.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cAMP-specific 3',5'-cyclic phosphodiesterase 4B353Homo sapiensMutation(s): 3 
Gene Names: PDE4BDPDE4
EC: 3.1.4.17
UniProt & NIH Common Fund Data Resources
Find proteins for Q07343 (Homo sapiens)
Explore Q07343 
Go to UniProtKB:  Q07343
PHAROS:  Q07343
GTEx:  ENSG00000184588 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07343
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ZG2
Query on ZG2

Download Ideal Coordinates CCD File 
G [auth A]5-[5-benzyl-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazol-2-yl]-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine
C29 H34 N6 O3
XOLUUYCIKUMYDW-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
H [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ARS
Query on ARS

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A]
ARSENIC
As
RBFQJDQYXXHULB-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ZG2 PDBBind:  3O57 IC50: 0.08 (nM) from 1 assay(s)
Binding MOAD:  3O57 IC50: 0.08 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 
  • Space Group: I 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.622α = 90
b = 94.907β = 90
c = 105.853γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-08-03
    Type: Initial release
  • Version 1.1: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description