4ZZN

Human ERK2 in complex with an inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.33 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of Erk1/2.

Ward, R.A.Colclough, N.Challinor, M.Debreczeni, J.Eckersley, K.Fairley, G.Feron, L.Flemington, V.Graham, M.A.Greenwood, R.Hopcroft, P.Howard, T.D.James, M.Jones, C.D.Jones, C.R.Renshaw, J.Roberts, K.Snow, L.Tonge, M.Yeung, K.

(2015) J Med Chem 58: 4790

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00466
  • Primary Citation of Related Structures:  
    4ZZM, 4ZZN, 4ZZO

  • PubMed Abstract: 

    The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
MITOGEN-ACTIVATED PROTEIN KINASE 1350Homo sapiensMutation(s): 0 
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CQ8
Query on CQ8

Download Ideal Coordinates CCD File 
C [auth A]2-[[5-chloranyl-2-(oxan-4-ylamino)pyridin-4-yl]amino]-N-methyl-benzamide
C18 H21 Cl N4 O2
OYYNQAPQYQZOFQ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
Binding Affinity Annotations 
IDSourceBinding Affinity
CQ8 BindingDB:  4ZZN IC50: min: 260, max: 7500 (nM) from 2 assay(s)
Binding MOAD:  4ZZN IC50: 260 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.33 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.175 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.76α = 90
b = 69.7β = 108.71
c = 59.8γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2015-05-27
    Type: Initial release
  • Version 1.1: 2015-08-26
    Changes: Database references