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 

Starting Model: experimental
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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. [email protected]


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

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

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