5J7S

Crystal structure of SM1-71 bound to TAK1-TAB1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.37 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.228 
  • R-Value Observed: 0.229 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structure-guided development of covalent TAK1 inhibitors.

Tan, L.Gurbani, D.Weisberg, E.L.Hunter, J.C.Li, L.Jones, D.S.Ficarro, S.B.Mowafy, S.Tam, C.P.Rao, S.Du, G.Griffin, J.D.Sorger, P.K.Marto, J.A.Westover, K.D.Gray, N.S.

(2017) Bioorg Med Chem 25: 838-846

  • DOI: https://doi.org/10.1016/j.bmc.2016.11.035
  • Primary Citation of Related Structures:  
    5E7R, 5J7S, 5J8I, 5J9L, 5JH6, 5JK3

  • PubMed Abstract: 

    TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol.


  • Organizational Affiliation

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, 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 chimera314Homo 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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6H3
Query on 6H3

Download Ideal Coordinates CCD File 
B [auth A]N-{2-[(5-chloro-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]phenyl}propanamide
C24 H28 Cl N7 O
IIMJCIGRKJCCHT-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6H3 BindingDB:  5J7S IC50: 1630 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.37 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.228 
  • R-Value Observed: 0.229 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.234α = 90
b = 134.06β = 90
c = 146.814γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Cancer Prevention and Research Institute of Texas (CPRIT)United StatesCPRIT R1207 and CPRIT RP140233

Revision History  (Full details and data files)

  • Version 1.0: 2017-02-15
    Type: Initial release
  • Version 1.1: 2017-09-27
    Changes: Author supporting evidence
  • Version 1.2: 2020-01-08
    Changes: Author supporting evidence
  • Version 1.3: 2023-09-27
    Changes: Data collection, Database references, Refinement description
  • Version 1.4: 2024-11-06
    Changes: Structure summary