5B4K

Crystal structure of the catalytic domain of human PDE10A complexed with N-(4-((5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)oxy)phenyl)-1H-benzimidazol-2-amine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.181 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket

Yoshikawa, M.Hitaka, T.Hasui, T.Fushimi, M.Kunitomo, J.Kokubo, H.Oki, H.Nakashima, K.Taniguchi, T.

(2016) Bioorg Med Chem 24: 3447-3455

  • DOI: https://doi.org/10.1016/j.bmc.2016.05.049
  • Primary Citation of Related Structures:  
    5B4K, 5B4L

  • PubMed Abstract: 

    Utilizing structure-based drug design techniques, we designed and synthesized phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These compounds can interact with Tyr683 in the PDE10A selectivity pocket. Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A selectivity pocket. After optimizing the linker length, we identified 1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (16f) as having highly potent PDE10A inhibitory activity (IC50=0.76nM) and perfect selectivity against other PDEs (>13,000-fold, IC50=>10,000nM). The crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety was located deep within the PDE10A selectivity pocket and interacted with Tyr683. Additionally, a bidentate interaction existed between the 5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs.


  • Organizational Affiliation

    Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: masato.yoshikawa@takeda.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 10A
A, B
338Homo sapiensMutation(s): 0 
Gene Names: PDE10A
EC: 3.1.4.17
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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.181 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.734α = 90
b = 81.683β = 90
c = 161.654γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
MOLREPphasing
Cootmodel building

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-06-29
    Type: Initial release
  • Version 1.1: 2016-08-03
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description