1ZKL

Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.194 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7

Wang, H.Liu, Y.Chen, Y.Robinson, H.Ke, H.

(2005) J Biol Chem 280: 30949-30955

  • DOI: https://doi.org/10.1074/jbc.M504398200
  • Primary Citation of Related Structures:  
    1ZKL

  • PubMed Abstract: 

    Phosphodiesterase (PDE) inhibitors have been widely studied as therapeutics for treatment of human diseases. However, the mechanism by which each PDE family recognizes selectively a category of inhibitors remains a puzzle. Here we report the crystal structure of PDE7A1 catalytic domain in complex with non-selective inhibitor 3-isobutyl-1-methylxanthine and kinetic analysis on the mutants of PDE7A1 and PDE4D2. Our studies suggest at least three elements play critical roles in inhibitor selectivity: 1) the conformation and position of an invariant glutamine, 2) the natures of scaffolding residues, and 3) residues that alter shape and size of the binding pocket. Kinetic analysis shows that single PDE7 to PDE4 mutations increase the sensitivity of PDE7 to PDE4 inhibitors but are not sufficient to render the engineered enzymes comparable with the wild types. The triple S373Y/S377T/I412S mutation of PDE7A1 produces a PDE4-like enzyme, implying that multiple elements must work together to determine inhibitor selectivity.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
High-affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A353Homo sapiensMutation(s): 0 
Gene Names: PDE7A
EC: 3.1.4.17 (PDB Primary Data), 3.1.4.53 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q13946 (Homo sapiens)
Explore Q13946 
Go to UniProtKB:  Q13946
PHAROS:  Q13946
GTEx:  ENSG00000205268 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13946
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
IBM BindingDB:  1ZKL Ki: 4000 (nM) from 1 assay(s)
IC50: 8.56e+4 (nM) from 1 assay(s)
PDBBind:  1ZKL IC50: 8100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.194 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 115.751α = 90
b = 115.751β = 90
c = 64.29γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-07-05
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2024-02-14
    Changes: Data collection, Database references, Derived calculations