1TVO

The structure of ERK2 in complex with a small molecule inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.263 
  • R-Value Observed: 0.265 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex

Ohori, M.Kinoshita, T.Okubo, M.Sato, K.Yamazaki, A.Arakawa, H.Nishimura, S.Inamura, N.Nakajima, H.Neya, M.Miyake, H.Fujii, T.

(2005) Biochem Biophys Res Commun 336: 357-363

  • DOI: https://doi.org/10.1016/j.bbrc.2005.08.082
  • Primary Citation of Related Structures:  
    1TVO

  • PubMed Abstract: 

    Selective inhibition of extracellular signal-regulated kinase (ERK) represents a potential approach for the treatment of cancer and other diseases; however, no selective inhibitors are currently available. Here, we describe an ERK-selective inhibitor, FR180204, and determine the structural basis of its selectivity. FR180204 inhibited the kinase activity of ERK1 and ERK2, with K(i) values 0.31 and 0.14microM, respectively. Lineweaver-Burk analysis of the binding interaction revealed that FR180204 acted as competitive inhibitor of ATP. In mink lung epithelial Mv1Lu cells, FR180204 inhibited TGFbeta-induced luciferase-expression. X-ray crystal structure analysis of the human ERK2/FR180204 complex revealed that Q105, D106, L156, and C166, which form the ATP-binding pocket on ERK, play important roles in the drug/protein interaction. These results suggest that FR180204 is an ERK-selective and cell-permeable inhibitor, and could be useful for elucidating the roles of ERK as well as for drug development.


  • Organizational Affiliation

    Lead Discovery Research Laboratories, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba, Ibaraki 305-8585, Japan. makoto.ohori@jp.astellas.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase 1368Homo sapiensMutation(s): 0 
EC: 2.7.1.37
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
FRZ
Query on FRZ

Download Ideal Coordinates CCD File 
B [auth A]5-(2-PHENYLPYRAZOLO[1,5-A]PYRIDIN-3-YL)-1H-PYRAZOLO[3,4-C]PYRIDAZIN-3-AMINE
C18 H13 N7
XVECMUKVOMUNLE-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FRZ Binding MOAD:  1TVO Ki: 140 (nM) from 1 assay(s)
BindingDB:  1TVO Ki: min: 310, max: 310 (nM) from 2 assay(s)
Kd: 850 (nM) from 1 assay(s)
IC50: min: 1200, max: 1900 (nM) from 2 assay(s)
PDBBind:  1TVO Ki: 140 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.263 
  • R-Value Observed: 0.265 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.86α = 90
b = 69.99β = 116.5
c = 63.3γ = 90
Software Package:
Software NamePurpose
CNXrefinement
CrystalCleardata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-09-13
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 1.4: 2024-03-13
    Changes: Data collection, Database references, Derived calculations