4QTA

Structure of human ERK2 in complex with SCH772984 revealing a novel inhibitor-induced binding pocket


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics.

Chaikuad, A.M C Tacconi, E.Zimmer, J.Liang, Y.Gray, N.S.Tarsounas, M.Knapp, S.

(2014) Nat Chem Biol 10: 853-860

  • DOI: https://doi.org/10.1038/nchembio.1629
  • Primary Citation of Related Structures:  
    4QTA, 4QTB, 4QTC, 4QTD, 4QTE

  • PubMed Abstract: 

    Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.


  • Organizational Affiliation

    Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 1361Homo sapiensMutation(s): 0 
Gene Names: ERK2MAPK1PRKM1PRKM2
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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
38Z
Query on 38Z

Download Ideal Coordinates CCD File 
L [auth A](3R)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]piperazin-1-yl}ethyl)-N-[3-(pyridin-4-yl)-2H-indazol-5-yl]pyrrolidine-3-carboxamide
C33 H33 N9 O2
HDAJDNHIBCDLQF-RUZDIDTESA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
B [auth A]
C [auth A]
D [auth A]
E [auth A]
F [auth A]
B [auth A],
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
38Z Binding MOAD:  4QTA Kd: 233 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.82α = 90
b = 75.54β = 90
c = 103.59γ = 90
Software Package:
Software NamePurpose
GDAdata collection
PHASERphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-23
    Type: Initial release
  • Version 1.1: 2014-09-24
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description