3G4I

Crystal structure of human phosphodiesterase 4d with d155871


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.

Burgin, A.B.Magnusson, O.T.Singh, J.Witte, P.Staker, B.L.Bjornsson, J.M.Thorsteinsdottir, M.Hrafnsdottir, S.Hagen, T.Kiselyov, A.S.Stewart, L.J.Gurney, M.E.

(2010) Nat Biotechnol 28: 63-70

  • DOI: https://doi.org/10.1038/nbt.1598
  • Primary Citation of Related Structures:  
    3G45, 3G4G, 3G4I, 3G4K, 3G4L, 3G58, 3IAD

  • PubMed Abstract: 

    Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.


  • Organizational Affiliation

    deCODE biostructures, Bainbridge Island, Washington, USA. aburgin@embios.com


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, C, D
381Homo sapiensMutation(s): 2 
Gene Names: PDE4DDPDE3
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
D71
Query on D71

Download Ideal Coordinates CCD File 
H [auth A],
O [auth B],
V [auth C],
Z [auth D]
1-(3-nitrophenyl)-3-(pyridin-4-ylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
C19 H13 N5 O4
YLHRMVRLIOIWTO-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
G [auth A],
N [auth B],
U [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
L [auth B],
S [auth C],
X [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EOH
Query on EOH

Download Ideal Coordinates CCD File 
AA [auth D]
I [auth A]
J [auth A]
K [auth A]
P [auth B]
AA [auth D],
I [auth A],
J [auth A],
K [auth A],
P [auth B],
Q [auth B],
R [auth B],
W [auth C]
ETHANOL
C2 H6 O
LFQSCWFLJHTTHZ-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
F [auth A],
M [auth B],
T [auth C],
Y [auth D]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
D71 PDBBind:  3G4I IC50: 0.91 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.865α = 90
b = 113.241β = 90
c = 161.22γ = 90
Software Package:
Software NamePurpose
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2010-01-19 
  • Deposition Author(s): Staker, B.L.

Revision History  (Full details and data files)

  • Version 1.0: 2010-01-19
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.3: 2024-02-21
    Changes: Data collection