6GL9

Crystal structure of JAK3 in complex with Compound 10 (FM475)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Development, Optimization, and Structure-Activity Relationships of Covalent-Reversible JAK3 Inhibitors Based on a Tricyclic Imidazo[5,4- d]pyrrolo[2,3- b]pyridine Scaffold.

Forster, M.Chaikuad, A.Dimitrov, T.Doring, E.Holstein, J.Berger, B.T.Gehringer, M.Ghoreschi, K.Muller, S.Knapp, S.Laufer, S.A.

(2018) J Med Chem 61: 5350-5366

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00571
  • Primary Citation of Related Structures:  
    6GL9, 6GLA, 6GLB

  • PubMed Abstract: 

    Janus kinases are major drivers of immune signaling and have been the focus of anti-inflammatory drug discovery for more than a decade. Because of the invariable colocalization of JAK1 and JAK3 at cytokine receptors, the question if selective JAK3 inhibition is sufficient to effectively block downstream signaling has been highly controversial. Recently, we discovered the covalent-reversible JAK3 inhibitor FM-381 (23) featuring high isoform and kinome selectivity. Crystallography revealed that this inhibitor induces an unprecedented binding pocket by interactions of a nitrile substituent with arginine residues in JAK3. Herein, we describe detailed structure-activity relationships necessary for induction of the arginine pocket and the impact of this structural change on potency, isoform selectivity, and efficacy in cellular models. Furthermore, we evaluated the stability of this novel inhibitor class in in vitro metabolic assays and were able to demonstrate an adequate stability of key compound 23 for in vivo use.


  • Organizational Affiliation

    Department of Pharmaceutical/Medicinal Chemistry , Eberhard Karls University Tübingen , Auf der Morgenstelle 8 , 72076 Tübingen , DE , Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK3
A, B
294Homo sapiensMutation(s): 0 
Gene Names: JAK3
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P52333 (Homo sapiens)
Explore P52333 
Go to UniProtKB:  P52333
PHAROS:  P52333
GTEx:  ENSG00000105639 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP52333
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
F3W
Query on F3W

Download Ideal Coordinates CCD File 
C [auth A],
M [auth B]
(~{E})-3-[3-(3-cyclohexyl-3,5,8,10-tetrazatricyclo[7.3.0.0^{2,6}]dodeca-1(9),2(6),4,7,11-pentaen-4-yl)phenyl]prop-2-enenitrile
C23 H21 N5
JIDRJSPIWPPOBL-FNORWQNLSA-N
PHU
Query on PHU

Download Ideal Coordinates CCD File 
D [auth A],
N [auth B]
1-phenylurea
C7 H8 N2 O
LUBJCRLGQSPQNN-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A],
O [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
I [auth A]
J [auth A]
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
T [auth B],
U [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
F3W Binding MOAD:  6GL9 IC50: 135 (nM) from 1 assay(s)
BindingDB:  6GL9 IC50: 135 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.02α = 91.93
b = 50.424β = 90.03
c = 61.588γ = 92.8
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2018-06-27
    Type: Initial release
  • Version 1.1: 2018-07-11
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description