6FYL

X-ray structure of CLK2-KD(136-496)/CX-4945 at 1.95A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

X-ray Structures and Feasibility Assessment of CLK2 Inhibitors for Phelan-McDermid Syndrome.

Kallen, J.Bergsdorf, C.Arnaud, B.Bernhard, M.Brichet, M.Cobos-Correa, A.Elhajouji, A.Freuler, F.Galimberti, I.Guibourdenche, C.Haenni, S.Holzinger, S.Hunziker, J.Izaac, A.Kaufmann, M.Leder, L.Martus, H.J.von Matt, P.Polyakov, V.Roethlisberger, P.Roma, G.Stiefl, N.Uteng, M.Lerchner, A.

(2018) ChemMedChem 13: 1997-2007

  • DOI: https://doi.org/10.1002/cmdc.201800344
  • Primary Citation of Related Structures:  
    6FYI, 6FYK, 6FYL, 6FYO, 6FYP, 6FYR, 6FYV

  • PubMed Abstract: 

    CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan-McDermid syndrome (PMDS). Herein, the discovery of a very potent indazole CLK inhibitor series and the CLK2 X-ray structure of the most potent analogue are reported. This new indazole series was identified through a biochemical CLK2 Caliper assay screen with 30k compounds selected by an in silico approach. Novel high-resolution X-ray structures of all CLKs, including the first CLK4 X-ray structure, bound to known CLK2 inhibitor tool compounds (e.g., TG003, CX-4945), are also shown and yield insight into inhibitor selectivity in the CLK family. The efficacy of the new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. Genotoxicity findings in the human lymphocyte micronucleus test (MNT) assay are shown by using two structurally different CLK inhibitors to reveal a major concern for pan-CLK inhibition in PMDS.


  • Organizational Affiliation

    Novartis Institutes for BioMedical Research, Novartis Campus, 4002, Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dual specificity protein kinase CLK2363Homo sapiensMutation(s): 0 
Gene Names: CLK2
EC: 2.7.12.1
UniProt & NIH Common Fund Data Resources
Find proteins for P49760 (Homo sapiens)
Explore P49760 
Go to UniProtKB:  P49760
PHAROS:  P49760
GTEx:  ENSG00000176444 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49760
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3NG
Query on 3NG

Download Ideal Coordinates CCD File 
B [auth A]5-[(3-chlorophenyl)amino]benzo[c][2,6]naphthyridine-8-carboxylic acid
C19 H12 Cl N3 O2
MUOKSQABCJCOPU-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3NG BindingDB:  6FYL IC50: min: 3.8, max: 4 (nM) from 2 assay(s)
Binding MOAD:  6FYL IC50: 7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.631α = 90
b = 75.997β = 90
c = 111.701γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2018-07-18 
  • Deposition Author(s): Kallen, J.

Revision History  (Full details and data files)

  • Version 1.0: 2018-07-18
    Type: Initial release
  • Version 1.1: 2018-09-12
    Changes: Data collection, Database references
  • Version 1.2: 2018-09-26
    Changes: Data collection, Database references
  • Version 1.3: 2018-10-03
    Changes: Data collection
  • Version 1.4: 2019-11-06
    Changes: Data collection, Database references
  • Version 1.5: 2024-01-17
    Changes: Data collection, Database references, Refinement description