4QTB

Structure of human ERK1 in complex with SCH772984 revealing a novel inhibitor-induced binding pocket


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.175 
  • R-Value Work: 0.147 
  • R-Value Observed: 0.148 

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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 3
A, B
380Homo sapiensMutation(s): 0 
Gene Names: ERK1MAPK3PRKM3
EC: 2.7.11.24
UniProt & NIH Common Fund Data Resources
Find proteins for P27361 (Homo sapiens)
Explore P27361 
Go to UniProtKB:  P27361
PHAROS:  P27361
GTEx:  ENSG00000102882 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27361
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
38Z
Query on 38Z

Download Ideal Coordinates CCD File 
FA [auth B],
T [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 
EA [auth B],
S [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
DMS
Query on DMS

Download Ideal Coordinates CCD File 
BA [auth B],
P [auth A],
Q [auth A]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth B]
C [auth A]
D [auth A]
E [auth A]
F [auth A]
AA [auth B],
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
U [auth B],
V [auth B],
W [auth B],
X [auth B],
Y [auth B],
Z [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
CA [auth B],
DA [auth B],
R [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
38Z Binding MOAD:  4QTB Kd: 213 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.175 
  • R-Value Work: 0.147 
  • R-Value Observed: 0.148 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 61.98α = 90
b = 94.01β = 91.71
c = 65.36γ = 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 

Deposition Data

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