5N87

TTK kinase domain in complex with NTRC 0066-0


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity.

Uitdehaag, J.C.M.de Man, J.Willemsen-Seegers, N.Prinsen, M.B.W.Libouban, M.A.A.Sterrenburg, J.G.de Wit, J.J.P.de Vetter, J.R.F.de Roos, J.A.D.M.Buijsman, R.C.Zaman, G.J.R.

(2017) J Mol Biol 429: 2211-2230

  • DOI: https://doi.org/10.1016/j.jmb.2017.05.014
  • Primary Citation of Related Structures:  
    5N7V, 5N84, 5N87, 5N93, 5N9S, 5NA0, 5NAD

  • PubMed Abstract: 

    The protein kinase threonine tyrosine kinase (TTK; also known as Mps1) is a critical component of the spindle assembly checkpoint and a promising drug target for the treatment of aggressive cancers, such as triple negative breast cancer. While the first TTK inhibitors have entered clinical trials, little is known about how the inhibition of TTK with small-molecule compounds affects cellular activity. We studied the selective TTK inhibitor NTRC 0066-0, which was developed in our own laboratory, together with 11 TTK inhibitors developed by other companies, including Mps-BAY2b, BAY 1161909, BAY 1217389 (Bayer), TC-Mps1-12 (Shionogi), and MPI-0479605 (Myrexis). Parallel testing shows that the cellular activity of these TTK inhibitors correlates with their binding affinity to TTK and, more strongly, with target residence time. TTK inhibitors are therefore an example where target residence time determines activity in in vitro cellular assays. X-ray structures and thermal stability experiments reveal that the most potent compounds induce a shift of the glycine-rich loop as a result of binding to the catalytic lysine at position 553. This "lysine trap" disrupts the catalytic machinery. Based on these insights, we developed TTK inhibitors, based on a (5,6-dihydro)pyrimido[4,5-e]indolizine scaffold, with longer target residence times, which further exploit an allosteric pocket surrounding Lys553. Their binding mode is new for kinase inhibitors and can be classified as hybrid Type I/Type III. These inhibitors have very potent anti-proliferative activity that rivals classic cytotoxic therapy. Our findings will open up new avenues for more applications for TTK inhibitors in cancer treatment.


  • Organizational Affiliation

    Netherlands Translational Research Center B.V., Kloosterstraat 9, 5349AB Oss, The Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dual specificity protein kinase TTK313Homo sapiensMutation(s): 0 
Gene Names: TTKMPS1MPS1L1
EC: 2.7.12.1
UniProt & NIH Common Fund Data Resources
Find proteins for P33981 (Homo sapiens)
Explore P33981 
Go to UniProtKB:  P33981
PHAROS:  P33981
GTEx:  ENSG00000112742 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP33981
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
N66
Query on N66

Download Ideal Coordinates CCD File 
B [auth A]~{N}-(2,6-diethylphenyl)-2-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide
C33 H39 N7 O2
HGEIUFJVGHMGRR-UHFFFAOYSA-N
PGF
Query on PGF

Download Ideal Coordinates CCD File 
C [auth A]2,5,8,11-TETRAOXATRIDECANE
C9 H20 O4
JRRDISHSXWGFRF-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
D [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
N66 Binding MOAD:  5N87 Kd: 0.56 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.09α = 90
b = 112.23β = 90
c = 113.98γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
Aimlessdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-31
    Type: Initial release
  • Version 1.1: 2017-06-07
    Changes: Database references
  • Version 1.2: 2017-07-05
    Changes: Database references
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Derived calculations, Refinement description