5O8U

Covalent Inhibitor 4b bound to the Lipid Pocket of p38alpha Mutant S252C


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Covalent Lipid Pocket Ligands Targeting p38 alpha MAPK Mutants.

Buhrmann, M.Hardick, J.Weisner, J.Quambusch, L.Rauh, D.

(2017) Angew Chem Int Ed Engl 56: 13232-13236

  • DOI: https://doi.org/10.1002/anie.201706345
  • Primary Citation of Related Structures:  
    5O8U, 5O8V

  • PubMed Abstract: 

    A chemical genetic approach is presented to covalently target a unique lipid binding pocket in the protein kinase p38α, whose function is not yet known. Based on a series of cocrystal structures, a library of 2-arylquinazolines that were decorated with electrophiles were designed and synthesized to covalently target tailored p38α mutants containing artificially introduced cysteine residues. Matching protein-ligand pairs were identified by MS analysis and further validated by MS/MS studies and protein crystallography. The covalent ligands that emerged from this approach showed excellent selectivity towards a single p38α mutant and will be applicable as suitable probes in future studies of biological systems to dissect the function of the lipid pocket by means of pharmacological perturbations.


  • Organizational Affiliation

    Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 14360Homo sapiensMutation(s): 1 
Gene Names: MAPK14CSBPCSBP1CSBP2CSPB1MXI2SAPK2A
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for Q16539 (Homo sapiens)
Explore Q16539 
Go to UniProtKB:  Q16539
PHAROS:  Q16539
GTEx:  ENSG00000112062 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16539
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9O5
Query on 9O5

Download Ideal Coordinates CCD File 
B [auth A]4-[3-[7-azanyl-4-(2-phenylethylamino)quinazolin-2-yl]phenyl]butan-2-one
C26 H26 N4 O
KBMFFRCBXRMQHN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.58α = 90
b = 74.05β = 90
c = 76.71γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-09-06
    Type: Initial release
  • Version 1.1: 2017-10-25
    Changes: Database references
  • Version 1.2: 2018-05-02
    Changes: Data collection
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Refinement description