6IJI

Crystal structure of PDE10 in complex with inhibitor 2b


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.341 
  • R-Value Work: 0.258 
  • R-Value Observed: 0.262 

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This is version 1.2 of the entry. See complete history


Literature

Validation of Phosphodiesterase-10 as a Novel Target for Pulmonary Arterial Hypertension via Highly Selective and Subnanomolar Inhibitors.

Huang, Y.Y.Yu, Y.F.Zhang, C.Chen, Y.Zhou, Q.Li, Z.Zhou, S.Li, Z.Guo, L.Wu, D.Wu, Y.Luo, H.B.

(2019) J Med Chem 62: 3707-3721

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00224
  • Primary Citation of Related Structures:  
    6IJH, 6IJI

  • PubMed Abstract: 

    Pulmonary arterial hypertension (PAH) causes pathological increase in pulmonary vascular resistance, leading to right-heart failure and eventual death. Previously, phosphodiesterase-10 (PDE10) was reported to be a promising target for PAH based on the studies with a nonselective PDE inhibitor papaverine, but little progress has been made to confirm the practical application of PDE10 inhibitors. To validate whether PAH is ameliorated by PDE10 inhibition rather than other PDE isoforms, here we report an integrated strategy to discover highly selective PDE10 inhibitors as chemical probes. Structural optimization resulted in a PDE10 inhibitor 2b with subnanomolar affinity and good selectivity of >45 000-fold against other PDEs. The cocrystal structure of the PDE10-2b complex revealed an important H-bond interaction between 2b and Tyr693. Finally, compound 2b significantly decreased the arterial pressure in PAH rats and thus validated the potential of PDE10 as a novel anti-PAH target. These findings suggest that PDE10 inhibition may be a viable treatment option for PAH.


  • Organizational Affiliation

    School of Pharmaceutical Sciences , Sun Yat-sen University , Guangzhou 510006 , China.


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 10A
A, B
324Homo 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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.341 
  • R-Value Work: 0.258 
  • R-Value Observed: 0.262 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.941α = 90
b = 159.455β = 90
c = 81.65γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CrysalisProdata reduction
CrysalisProdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Natural Science Foundation of ChinaChina81522041
National Natural Science Foundation of ChinaChina21572279
National Natural Science Foundation of ChinaChina81602955
National Natural Science Foundation of ChinaChina21402243

Revision History  (Full details and data files)

  • Version 1.0: 2019-04-10
    Type: Initial release
  • Version 1.1: 2019-04-24
    Changes: Data collection, Database references
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Derived calculations, Refinement description