4XJ0

Crystal structure of ERK2 in complex with an inhibitor 14K

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.58 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 

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This is version 1.1 of the entry. See complete history. 


Literature

Discovery of highly potent, selective, and efficacious small molecule inhibitors of ERK1/2.

Ren, L., Grina, J., Moreno, D., Blake, J.F., Gaudino, J.J., Garrey, R., Metcalf, A.T., Burkard, M., Martinson, M., Rasor, K., Chen, H., Dean, B., Gould, S.E., Pacheco, P., Shahidi-Latham, S., Yin, J., West, K., Wang, W., Moffat, J.G., Schwarz, J.B.

(2015) J Med Chem 58: 1976-1991

  • DOI: https://doi.org/10.1021/jm501921k
  • Primary Citation of Related Structures:  
    4XJ0

  • PubMed Abstract: 

    Using structure-based design, a novel series of pyridone ERK1/2 inhibitors was developed. Optimization led to the identification of (S)-14k, a potent, selective, and orally bioavailable agent that inhibited tumor growth in mouse xenograft models. On the basis of its in vivo efficacy and preliminary safety profiles, (S)-14k was selected for further preclinical evaluation.

    • Organizational Affiliation: 

    Array BioPharma Inc, 3200 Walnut Street, Boulder, Colorado 80301, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 1
A, B
349Homo sapiensMutation(s): 0 
Gene Names: MAPK1, ERK2, PRKM1, PRKM2
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for P28482 (Homo sapiens)
Explore P28482 
Go to UniProtKB:  P28482
PHAROS:  P28482
GTEx:  ENSG00000100030 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28482
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
41B
Query on 41B
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl]pyridin-2(1H)-one
C22 H22 Cl F N4 O3
PGGLRAWFUJMQBN-HXUWFJFHSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
NEP
Query on NEP
A, B
L-PEPTIDE LINKINGC6 H10 N3 O5 PHIS
Binding Affinity Annotations 
IDSourceBinding Affinity
41B BindingDB:  4XJ0 Ki: min: 0.4, max: 0.6 (nM) from 2 assay(s)
IC50: min: 1.1, max: 3.9 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.58 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.191α = 90
b = 83.191β = 90
c = 274.493γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-16
    Type: Initial release
  • Version 1.1: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description