4KBA

CK1d in complex with 9-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Ligand-protein interactions of selective casein kinase 1 delta inhibitors.

Mente, S.Arnold, E.Butler, T.Chakrapani, S.Chandrasekaran, R.Cherry, K.Dirico, K.Doran, A.Fisher, K.Galatsis, P.Green, M.Hayward, M.Humphrey, J.Knafels, J.Li, J.Liu, S.Marconi, M.McDonald, S.Ohren, J.Paradis, V.Sneed, B.Walton, K.Wager, T.

(2013) J Med Chem 56: 6819-6828

  • DOI: https://doi.org/10.1021/jm4006324
  • Primary Citation of Related Structures:  
    4KB8, 4KBA, 4KBC, 4KBK

  • PubMed Abstract: 

    Casein kinase 1δ (CK1δ) and 1ε (CK1ε) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On the basis of our previously published work demonstrating a CK1ε-preferring compound to be an ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1δ isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1δ and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1δ at sufficient central exposure levels is capable of modulating circadian rhythms.


  • Organizational Affiliation

    Pfizer Worldwide Research and Development , 700 Main Street, Cambridge, Massachusetts 02139, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Casein kinase I isoform delta
A, B, C, D
331Homo sapiensMutation(s): 0 
Gene Names: CSNK1DHCKID
EC: 2.7.11.1 (PDB Primary Data), 2.7.11.26 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P48730 (Homo sapiens)
Explore P48730 
Go to UniProtKB:  P48730
PHAROS:  P48730
GTEx:  ENSG00000141551 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP48730
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1QM
Query on 1QM

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C],
N [auth D]
9-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine
C18 H17 F N4 O
RDUXJEGWTNOYDA-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
I [auth B]
J [auth B]
L [auth C]
F [auth A],
G [auth A],
I [auth B],
J [auth B],
L [auth C],
M [auth C],
O [auth D],
P [auth D],
Q [auth D]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
1QM BindingDB:  4KBA IC50: min: 6, max: 42 (nM) from 3 assay(s)
PDBBind:  4KBA IC50: 6 (nM) from 1 assay(s)
Binding MOAD:  4KBA IC50: 6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.689α = 108
b = 83.964β = 105.71
c = 89.29γ = 93
Software Package:
Software NamePurpose
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2013-09-18 
  • Deposition Author(s): Liu, S.

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-18
    Type: Initial release
  • Version 1.1: 2013-09-25
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations