1XON

Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Piclamilast


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural Basis for the Activity of Drugs that Inhibit Phosphodiesterases.

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

(2004) Structure 12: 2233-2247

  • DOI: https://doi.org/10.1016/j.str.2004.10.004
  • Primary Citation of Related Structures:  
    1XLX, 1XLZ, 1XM4, 1XM6, 1XMU, 1XMY, 1XN0, 1XOM, 1XON, 1XOQ, 1XOR, 1XOS, 1XOT, 1XOZ, 1XP0

  • PubMed Abstract: 

    Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.


  • Organizational Affiliation

    Plexxikon, Inc., 91 Bolivar Drive, Berkeley, CA 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
PIL
Query on PIL

Download Ideal Coordinates CCD File 
CA [auth B],
E [auth A]
3-(CYCLOPENTYLOXY)-N-(3,5-DICHLOROPYRIDIN-4-YL)-4-METHOXYBENZAMIDE
C18 H18 Cl2 N2 O3
RRRUXBQSQLKHEL-UHFFFAOYSA-N
B3P
Query on B3P

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

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

Download Ideal Coordinates CCD File 
DA [auth B]
EA [auth B]
FA [auth B]
G [auth A]
GA [auth B]
DA [auth B],
EA [auth B],
FA [auth B],
G [auth A],
GA [auth B],
H [auth A],
HA [auth B],
I [auth A],
IA [auth B],
J [auth A],
JA [auth B],
K [auth A],
KA [auth B],
L [auth A],
LA [auth B],
M [auth A],
MA [auth B],
N [auth A],
NA [auth B],
O [auth A],
OA [auth B],
P [auth A],
PA [auth B],
Q [auth A],
QA [auth B],
R [auth A],
RA [auth B],
S [auth A],
T [auth A],
U [auth A],
V [auth A],
W [auth A],
X [auth A],
Y [auth A],
Z [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
BA [auth B],
D [auth A]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
PIL BindingDB:  1XON Ki: min: 0.4, max: 26 (nM) from 5 assay(s)
IC50: min: 0.02, max: 21 (nM) from 10 assay(s)
Binding MOAD:  1XON IC50: 0.02 (nM) from 1 assay(s)
PDBBind:  1XON IC50: 0.02 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.72 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.196α = 90
b = 78.877β = 90
c = 164.312γ = 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: 2004-12-14
    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