4HF4

Crystal Structure of PDE10A with a biaryl ether inhibitor (1-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)ethanol)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 

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Ligand Structure Quality Assessment 


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Literature

Discovery of selective biaryl ethers as PDE10A inhibitors: Improvement in potency and mitigation of Pgp-mediated efflux.

Rzasa, R.M.Hu, E.Rumfelt, S.Chen, N.Andrews, K.L.Chmait, S.Falsey, J.R.Zhong, W.Jones, A.D.Porter, A.Louie, S.W.Zhao, X.Treanor, J.J.Allen, J.R.

(2012) Bioorg Med Chem Lett 22: 7371-7375

  • DOI: https://doi.org/10.1016/j.bmcl.2012.10.078
  • Primary Citation of Related Structures:  
    4HEU, 4HF4

  • PubMed Abstract: 

    We report the discovery of a novel series of biaryl ethers as potent and selective PDE10A inhibitors. Structure-activity studies improved the potency and decreased Pgp-mediated efflux found in the initial compound 4. X-ray crystallographic studies revealed two novel binding modes to the catalytic site of the PDE10A enzyme.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. rrzasa@amgen.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
318Homo 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
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
15H
Query on 15H

Download Ideal Coordinates CCD File 
N [auth A],
X [auth B]
(1S)-1-(1-{3-[4-(1,3-benzothiazol-2-ylamino)phenoxy]pyrazin-2-yl}piperidin-4-yl)ethanol
C24 H25 N5 O2 S
GNWKATFENPQMIQ-INIZCTEOSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
Q [auth B],
R [auth B],
S [auth B],
T [auth B],
U [auth B],
V [auth B],
W [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
M [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
O [auth B],
P [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
15H PDBBind:  4HF4 Ki: 2.4 (nM) from 1 assay(s)
Binding MOAD:  4HF4 IC50: 2.4 (nM) from 1 assay(s)
BindingDB:  4HF4 IC50: 2.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.197 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 
  • Space Group: F 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 252.879α = 90
b = 252.879β = 90
c = 252.879γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata 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: 2012-12-12
    Type: Initial release