6HWT

Crystal structure of p38alpha in complex with a reduced photoswitchable 2-Azothiazol-based Inhibitor (compound 31)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.7 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.202 

wwPDB Validation 3D Report Full Report


This is version 1.0 of the entry. See complete history

Literature

2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach.

Schehr, M.Ianes, C.Weisner, J.Heintze, L.Muller, M.P.Pichlo, C.Charl, J.Brunstein, E.Ewert, J.Lehr, M.Baumann, U.Rauh, D.Knippschild, U.Peifer, C.Herges, R.

(2019) Photochem. Photobiol. Sci. --: --

  • DOI: 10.1039/c9pp00010k
  • Primary Citation of Related Structures:  

  • PubMed Abstract: 
  • In photopharmacology, photoswitchable compounds including azobenzene or other diarylazo moieties exhibit bioactivity against a target protein typically in the slender E-configuration, whereas the rather bulky Z-configuration usually is pharmacologica ...

    In photopharmacology, photoswitchable compounds including azobenzene or other diarylazo moieties exhibit bioactivity against a target protein typically in the slender E-configuration, whereas the rather bulky Z-configuration usually is pharmacologically less potent. Herein we report the design, synthesis and photochemical/inhibitory characterization of new photoswitchable kinase inhibitors targeting p38α MAPK and CK1δ. A well characterized inhibitor scaffold was used to attach arylazo- and diazocine moieties. When the isolated isomers, or the photostationary state (PSS) of isomers, were tested in commonly used in vitro kinase assays, however, only small differences in activity were observed. X-ray analyses of ligand-bound p38α MAPK and CK1δ complexes revealed dynamic conformational adaptations of the protein with respect to both isomers. More importantly, irreversible reduction of the azo group to the corresponding hydrazine was observed. Independent experiments revealed that reducing agents such as DTT (dithiothreitol) and GSH (glutathione) that are typically used for protein stabilization in biological assays were responsible. Two further sources of error are the concentration dependence of the E-Z-switching efficiency and artefacts due to incomplete exclusion of light during testing. Our findings may also apply to a number of previously investigated azobenzene-based photoswitchable inhibitors.


    Organizational Affiliation

    Otto Diels-Institute of Organic Chemistry, Christian Albrechts University Kiel, Otto-Hahn-Platz 4, 24118 Kiel, Germany. rherges@oc.uni-kiel.de.




Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Mitogen-activated protein kinase 14
A
362Homo sapiensMutation(s): 0 
Gene Names: MAPK14 (CSBP, CSBP1, CSBP2, CSPB1, MXI2, SAPK2A)
EC: 2.7.11.24
Find proteins for Q16539 (Homo sapiens)
Go to Gene View: MAPK14
Go to UniProtKB:  Q16539
Small Molecules
Ligands 2 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
GXH
Query on GXH

Download SDF File 
Download CCD File 
A
3-(2,5-dimethoxyphenyl)-~{N}-[4-[4-(4-fluorophenyl)-2-(2-phenylhydrazinyl)-1,3-thiazol-5-yl]pyridin-2-yl]propanamide
C31 H28 F N5 O3 S
IREZAYNVTNYSLH-UHFFFAOYSA-N
 Ligand Interaction
BOG
Query on BOG

Download SDF File 
Download CCD File 
A
B-OCTYLGLUCOSIDE
C14 H28 O6
HEGSGKPQLMEBJL-RKQHYHRCSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.7 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.202 
  • Space Group: P 21 21 21
Unit Cell:
Length (Å)Angle (°)
a = 69.510α = 90.00
b = 69.810β = 90.00
c = 74.570γ = 90.00
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIXrefinement

Structure Validation

View Full Validation Report or Ramachandran Plots



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Federal Ministry for Education and ResearchGermanyBMBF 01GS08104
German Federal Ministry for Education and ResearchGermany01ZX1303C

Revision History 

  • Version 1.0: 2019-04-17
    Type: Initial release