3UVP

Human p38 MAP Kinase in Complex with a Benzamide Substituted Benzosuberone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.297 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.220 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Targeting the Hinge Glycine Flip and the Activation Loop: Novel Approach to Potent p38 alpha Inhibitors.

Martz, K.E.Dorn, A.Baur, B.Schattel, V.Goettert, M.I.Mayer-Wrangowski, S.C.Rauh, D.Laufer, S.A.

(2012) J Med Chem 55: 7862-7874

  • DOI: https://doi.org/10.1021/jm300951u
  • Primary Citation of Related Structures:  
    3UVP

  • PubMed Abstract: 

    The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38α MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the "deep pocket", and the hinge glycine flip of the kinase. Potent inhibitors with IC(50) values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the "deep pocket" in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.


  • Organizational Affiliation

    Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 14360Homo sapiensMutation(s): 0 
Gene Names: MAPK14CSBPCSBP1CSBP2CSPB1MXI2
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
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
048
Query on 048

Download Ideal Coordinates CCD File 
B [auth A]N-{2-fluoro-5-[(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)amino]phenyl}benzamide
C24 H21 F N2 O2
ATBLOTYVKHVLPU-UHFFFAOYSA-N
BOG
Query on BOG

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
octyl beta-D-glucopyranoside
C14 H28 O6
HEGSGKPQLMEBJL-RKQHYHRCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
048 BindingDB:  3UVP IC50: 35 (nM) from 1 assay(s)
Binding MOAD:  3UVP IC50: 35 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.297 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.220 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64α = 90
b = 68.8β = 90
c = 74.8γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-07
    Type: Initial release
  • Version 1.1: 2013-01-16
    Changes: Database references, Structure summary
  • Version 1.2: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Database references, Derived calculations, Structure summary
  • Version 1.3: 2023-11-08
    Changes: Data collection, Database references, Refinement description, Structure summary