5V5N

Crystal structure of Takinib bound to TAK1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-alpha Inhibition for Cancer and Autoimmune Disease.

Totzke, J.Gurbani, D.Raphemot, R.Hughes, P.F.Bodoor, K.Carlson, D.A.Loiselle, D.R.Bera, A.K.Eibschutz, L.S.Perkins, M.M.Eubanks, A.L.Campbell, P.L.Fox, D.A.Westover, K.D.Haystead, T.A.J.Derbyshire, E.R.

(2017) Cell Chem Biol 24: 1029-1039.e7

  • DOI: https://doi.org/10.1016/j.chembiol.2017.07.011
  • Primary Citation of Related Structures:  
    5V5N

  • PubMed Abstract: 

    Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human disease. In certain cancers, TNF-α is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNF-α antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNF-α-mediated signaling. Here, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNF-α stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated and non-phosphorylated TAK1 that binds within the ATP-binding pocket and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNF-α-induced cell death, with general implications for cancer and autoimmune disease treatment.


  • Organizational Affiliation

    Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera307Homo sapiensMutation(s): 0 
Gene Names: MAP3K7TAK1TAB1MAP3K7IP1
EC: 2.7.11.25
UniProt & NIH Common Fund Data Resources
Find proteins for Q15750 (Homo sapiens)
Explore Q15750 
Go to UniProtKB:  Q15750
PHAROS:  Q15750
GTEx:  ENSG00000100324 
Find proteins for O43318 (Homo sapiens)
Explore O43318 
Go to UniProtKB:  O43318
PHAROS:  O43318
GTEx:  ENSG00000135341 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsO43318Q15750
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EDH
Query on EDH

Download Ideal Coordinates CCD File 
B [auth A]N~1~-(1-propyl-1,3-dihydro-2H-benzimidazol-2-ylidene)benzene-1,3-dicarboxamide
C18 H18 N4 O2
UOZVVPXKJGOFIG-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
EDH Binding MOAD:  5V5N IC50: 9.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.34α = 90
b = 134.227β = 90
c = 143.385γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-08-30
    Type: Initial release
  • Version 1.1: 2023-10-04
    Changes: Data collection, Database references, Refinement description