1Y2D

Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 1-(4-methoxy-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design

Card, G.L.Blasdel, L.England, B.P.Zhang, C.Suzuki, Y.Gillette, S.Fong, D.Ibrahim, P.N.Artis, D.R.Bollag, G.Milburn, M.V.Kim, S.-H.Schlessinger, J.Zhang, K.Y.J.

(2005) Nat Biotechnol 23: 201-207

  • DOI: https://doi.org/10.1038/nbt1059
  • Primary Citation of Related Structures:  
    1Y2B, 1Y2C, 1Y2D, 1Y2E, 1Y2H, 1Y2J, 1Y2K

  • PubMed Abstract: 

    Cyclic nucleotide phosphodiesterases (PDEs) comprise a large family of enzymes that regulate a variety of cellular processes. We describe a family of potent PDE4 inhibitors discovered using an efficient method for scaffold-based drug design. This method involves an iterative approach starting with low-affinity screening of compounds followed by high-throughput cocrystallography to reveal the molecular basis underlying the activity of the newly identified compounds. Through detailed structural analysis of the interaction of the initially discovered pyrazole carboxylic ester scaffold with PDE4D using X-ray crystallography, we identified three sites of chemical substitution and designed small selective libraries of scaffold derivatives with modifications at these sites. A 4,000-fold increase in the potency of this PDE4 inhibitor was achieved after only two rounds of chemical synthesis and the structural analysis of seven pyrazole derivatives bound to PDE4B or PDE4D, revealing the robustness of this approach for identifying new inhibitors that can be further developed into drug candidates.


  • Organizational Affiliation

    Plexxikon Inc., 91 Bolivar Dr., Berkeley, California 94710, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cAMP-specific 3',5'-cyclic phosphodiesterase 4D
A, B
349Homo sapiensMutation(s): 0 
Gene Names: PDE4D
EC: 3.1.4.17
UniProt & NIH Common Fund Data Resources
Find proteins for Q08499 (Homo sapiens)
Explore Q08499 
Go to UniProtKB:  Q08499
PHAROS:  Q08499
GTEx:  ENSG00000113448 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ08499
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
B3P
Query on B3P

Download Ideal Coordinates CCD File 
GA [auth B]2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL
C11 H26 N2 O6
HHKZCCWKTZRCCL-UHFFFAOYSA-N
4DE
Query on 4DE

Download Ideal Coordinates CCD File 
E [auth A],
T [auth B]
1-(4-METHOXYPHENYL)-3,5-DIMETHYL-1H-PYRAZOLE-4-CARBOXYLIC ACID ETHYL ESTER
C15 H18 N2 O3
ZDSXCFSUGVAQSB-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
R [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth B]
CA [auth B]
DA [auth B]
EA [auth B]
AA [auth B],
BA [auth B],
CA [auth B],
DA [auth B],
EA [auth B],
F [auth A],
FA [auth B],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A],
Q [auth A],
U [auth B],
V [auth B],
W [auth B],
X [auth B],
Y [auth B],
Z [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth A],
S [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4DE BindingDB:  1Y2D IC50: min: 2000, max: 2000 (nM) from 2 assay(s)
PDBBind:  1Y2D IC50: 2000 (nM) from 1 assay(s)
Binding MOAD:  1Y2D IC50: 2000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.804α = 90
b = 79.146β = 90
c = 164.617γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
Blu-Icedata collection
ELVESdata scaling
EPMRphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2005-03-01
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.3: 2024-02-14
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description