3LXG

Crystal structure of rat phosphodiesterase 10A in complex with ligand WEB-3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.179 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of imidazo[1,5-a]pyrido[3,2-e]pyrazines as a new class of phosphodiesterase 10A inhibitiors.

Hofgen, N.Stange, H.Schindler, R.Lankau, H.J.Grunwald, C.Langen, B.Egerland, U.Tremmel, P.Pangalos, M.N.Marquis, K.L.Hage, T.Harrison, B.L.Malamas, M.S.Brandon, N.J.Kronbach, T.

(2010) J Med Chem 53: 4399-4411

  • DOI: https://doi.org/10.1021/jm1002793
  • Primary Citation of Related Structures:  
    3LXG

  • PubMed Abstract: 

    Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.


  • Organizational Affiliation

    Biotie Therapies GmbH, Meissner Strasse 191, 01445 Radebeul, Germany. norbert.hoefgen@biotie.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A308Rattus norvegicusMutation(s): 0 
Gene Names: Pde10a
EC: 3.1.4.17 (PDB Primary Data), 3.1.4.35 (PDB Primary Data)
UniProt
Find proteins for Q9QYJ6 (Rattus norvegicus)
Explore Q9QYJ6 
Go to UniProtKB:  Q9QYJ6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9QYJ6
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
Z73 PDBBind:  3LXG IC50: 7.28 (nM) from 1 assay(s)
BindingDB:  3LXG IC50: min: 7, max: 32 (nM) from 4 assay(s)
Binding MOAD:  3LXG IC50: 7.28 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.179 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 120.149α = 90
b = 120.149β = 90
c = 83.119γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata 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: 2010-05-19
    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