5UWF

Crystal structure of human PDE10A in complex with inhibitor 16d

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.

Dyck, B., Branstetter, B., Gharbaoui, T., Hudson, A.R., Breitenbucher, J.G., Gomez, L., Botrous, I., Marrone, T., Barido, R., Allerston, C.K., Cedervall, E.P., Xu, R., Sridhar, V., Barker, R., Aertgeerts, K., Schmelzer, K., Neul, D., Lee, D., Massari, M.E., Andersen, C.B., Sebring, K., Zhou, X., Petroski, R., Limberis, J., Augustin, M., Chun, L.E., Edwards, T.E., Peters, M., Tabatabaei, A.

(2017) J Med Chem 60: 3472-3483

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00302
  • Primary Citation of Related Structures:  
    5UOY, 5UP0, 5UWF

  • PubMed Abstract: 

    A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyrido[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory.

    • Organizational Affiliation: 

    Dart Neuroscience LLC , 12278 Scripps Summit Drive, San Diego, California 92131, United States.


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 10AA [auth C],
B [auth D]		344Homo sapiensMutation(s): 0 
Gene Names: PDE10A
EC: 3.1.4.17 (PDB Primary Data), 3.1.4.35 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y233 (Homo sapiens)
Explore Q9Y233 
Go to UniProtKB:  Q9Y233
PHAROS:  Q9Y233
GTEx:  ENSG00000112541 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y233
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
8Q7 BindingDB:  5UWF IC50: 59 (nM) from 1 assay(s)
Binding MOAD:  5UWF IC50: 59 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.718α = 90
b = 81.239β = 90
c = 158.609γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-04-26
    Type: Initial release
  • Version 1.1: 2017-05-10
    Changes: Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description