2X9E

HUMAN MPS1 IN COMPLEX WITH NMS-P715

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.306 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.215 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history. 


Literature

Targeting the Mitotic Checkpoint for Cancer Therapy with Nms-P715, an Inhibitor of Mps1 Kinase.

Colombo, R., Caldarelli, M., Mennecozzi, M., Giorgini, M.L., Sola, F., Cappella, P., Perrera, C., Depaolini, S.R., Rusconi, L., Cucchi, U., Avanzi, N., Bertrand, J.A., Bossi, R.T., Pesenti, E., Galvani, A., Isacchi, A., Colotta, F., Donati, D., Moll, J.

(2010) Cancer Res 70: 10255

  • DOI: https://doi.org/10.1158/0008-5472.CAN-10-2101
  • Primary Citation of Related Structures:  
    2X9E

  • PubMed Abstract: 

    MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells.

    • Organizational Affiliation: 

    Department of Cell Biology-Oncology, Nerviano Medical Sciences, Viale Pasteur 10, Nerviano 20014, Italy. riccardo.colombo@nervianoms.com


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DUAL SPECIFICITY PROTEIN KINASE TTK317Homo sapiensMutation(s): 0 
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SVE
Query on SVE
Download Ideal Coordinates CCD File 
B [auth A]N-(2,6-DIETHYLPHENYL)-1-METHYL-8-({4-[(1-METHYLPIPERIDIN-4-YL)CARBAMOYL]-2-(TRIFLUOROMETHOXY)PHENYL}AMINO)-4,5-DIHYDRO-1H-PYRAZOLO[4,3-H]QUINAZOLINE-3-CARBOXAMIDE
C35 H39 F3 N8 O3
JFOAJUGFHDCBJJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
SVE BindingDB:  2X9E IC50: min: 0.63, max: 182 (nM) from 5 assay(s)
PDBBind:  2X9E IC50: 182 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.306 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.215 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 105.665α = 90
b = 113.362β = 90
c = 72.485γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-12-29
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-03-27
    Changes: Data collection, Other, Source and taxonomy
  • Version 1.4: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description