3G45

Crystal structure of human phosphodiesterase 4b with regulatory domain and d155988


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.63 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 

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 4B
A, B
421Homo sapiensMutation(s): 0 
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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.63 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 
  • Space Group: P 31
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 95.004α = 90
b = 95.004β = 90
c = 93.714γ = 120
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: 2017-07-26
    Changes: Refinement description, Source and taxonomy
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations