2QYK

Crystal structure of PDE4A10 in complex with inhibitor NPV


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.201 

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This is version 1.2 of the entry. See complete history


Literature

Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors.

Wang, H.Peng, M.S.Chen, Y.Geng, J.Robinson, H.Houslay, M.D.Cai, J.Ke, H.

(2007) Biochem J 408: 193-201

  • DOI: https://doi.org/10.1042/BJ20070970
  • Primary Citation of Related Structures:  
    2QYK, 2QYL, 2QYM, 2QYN

  • PubMed Abstract: 

    PDE4 (phosphodiesterase-4)-selective inhibitors have attracted much attention as potential therapeutics for the treatment of both depression and major inflammatory diseases, but their practical application has been compromised by side effects. A possible cause for the side effects is that current PDE4-selective inhibitors similarly inhibit isoforms from all four PDE4 subfamilies. The development of PDE4 subfamily-selective inhibitors has been hampered by a lack of structural information. In the present study, we rectify this by providing the crystal structures of the catalytic domains of PDE4A, PDE4B and PDE4D in complex with the PDE4 inhibitor NVP {4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid} as well as the unliganded PDE4C structure. NVP binds in the same conformation to the deep cAMP substrate pocket and interacts with the same residues in each instance. However, detailed structural comparison reveals significant conformational differences. Although the active sites of PDE4B and PDE4D are mostly comparable, PDE4A shows significant displacements of the residues next to the invariant glutamine residue that is critical for substrate and inhibitor binding. PDE4C appears to be more distal from other PDE4 subfamilies, with certain key residues being disordered. Our analyses provide the first structural basis for the development of PDE4 subfamily-selective inhibitors.


  • Organizational Affiliation

    Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7260, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclic AMP-specific phosphodiesterase HSPDE4A10
A, B
335Homo sapiensMutation(s): 0 
Gene Names: PDE4A
UniProt & NIH Common Fund Data Resources
Find proteins for P27815 (Homo sapiens)
Explore P27815 
Go to UniProtKB:  P27815
PHAROS:  P27815
GTEx:  ENSG00000065989 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27815
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
NPV BindingDB:  2QYK IC50: min: 0.6, max: 3300 (nM) from 6 assay(s)
EC50: 20 (nM) from 1 assay(s)
PDBBind:  2QYK IC50: 3300 (nM) from 1 assay(s)
Binding MOAD:  2QYK IC50: 3300 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.201 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 105.443α = 90
b = 105.443β = 90
c = 166.103γ = 90
Software Package:
Software NamePurpose
AMoREphasing
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-04-08
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations