4B99

Crystal Structure of MAPK7 (ERK5) with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.225 

Starting Model: experimental
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This is version 1.4 of the entry. See complete history


Literature

X-Ray Crystal Structure of Erk5 (Mapk7) in Complex with a Specific Inhibitor.

Elkins, J.M.Wang, J.Deng, X.Pattison, M.J.Arthur, S.Erazo, T.Gomez, N.Lizcano, J.M.Gray, N.S.Knapp, S.

(2013) J Med Chem 56: 4413

  • DOI: https://doi.org/10.1021/jm4000837
  • Primary Citation of Related Structures:  
    4B99

  • PubMed Abstract: 

    The protein kinase ERK5 (MAPK7) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role mediating cell proliferation, survival, epithelial-mesenchymal transition, and angiogenesis. To date, no three-dimensional structure has been published that would allow rational design of inhibitors. To address this, we determined the X-ray crystal structure of the human ERK5 kinase domain in complex with a highly specific benzo[e]pyrimido[5,4-b]diazepine-6(11H)-one inhibitor. The structure reveals that specific residue differences in the ATP-binding site, compared to the related ERKs p38s and JNKs, allow for the development of ERK5-specific inhibitors. The selectivity of previously observed ERK5 inhibitors can also be rationalized using this structure, which provides a template for future development of inhibitors with potential for treatment of disease.


  • Organizational Affiliation

    Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
MITOGEN-ACTIVATED PROTEIN KINASE 7398Homo sapiensMutation(s): 0 
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for Q13164 (Homo sapiens)
Explore Q13164 
Go to UniProtKB:  Q13164
PHAROS:  Q13164
GTEx:  ENSG00000166484 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13164
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
R4L
Query on R4L

Download Ideal Coordinates CCD File 
B [auth A]11-cyclopentyl-2-[[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl-phenyl]amino]-5-methyl-pyrimido[4,5-b][1,4]benzodiazepin-6-one
C35 H44 N8 O3
OXSKLFUMHBJZNS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.225 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 95.15α = 90
b = 95.15β = 90
c = 119.45γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-09-19
    Type: Initial release
  • Version 1.1: 2013-05-22
    Changes: Database references
  • Version 1.2: 2013-06-26
    Changes: Database references
  • Version 1.3: 2018-01-24
    Changes: Structure summary
  • Version 1.4: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description