4C9X

Crystal structure of NUDT1 (MTH1) with S-crizotinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.182 
  • R-Value Work: 0.146 
  • R-Value Observed: 0.148 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Stereospecific Targeting of Mth1 by (S)-Crizotinib as an Anticancer Strategy.

Huber, K.V.M.Salah, E.Radic, B.Gridling, M.Elkins, J.M.Stukalov, A.Jemth, A.Gokturk, C.Sanjiv, K.Stromberg, K.Pham, T.Berglund, U.W.Colinge, J.Bennett, K.L.Loizou, J.I.Helleday, T.Knapp, S.Superti-Furga, G.

(2014) Nature 508: 222

  • DOI: https://doi.org/10.1038/nature13194
  • Primary Citation of Related Structures:  
    4C9W, 4C9X

  • PubMed Abstract: 

    Activated RAS GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small molecules, such as SCH51344, but their molecular mechanism of action remains generally unknown. Here, using a chemical proteomic approach, we identify the target of SCH51344 as the human mutT homologue MTH1 (also known as NUDT1), a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used (R)-enantiomer of the drug was inactive, whereas the (S)-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinome-wide activity surveys and MTH1 co-crystal structures of both enantiomers provide a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models. Our results propose (S)-crizotinib as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.


  • Organizational Affiliation

    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
7,8-DIHYDRO-8-OXOGUANINE TRIPHOSPHATASE158Homo sapiensMutation(s): 0 
EC: 3.6.1.55 (PDB Primary Data), 3.6.1.56 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P36639 (Homo sapiens)
Explore P36639 
Go to UniProtKB:  P36639
PHAROS:  P36639
GTEx:  ENSG00000106268 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP36639
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
VHS Binding MOAD:  4C9X Kd: 48 (nM) from 1 assay(s)
BindingDB:  4C9X IC50: min: 330, max: 1800 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.182 
  • R-Value Work: 0.146 
  • R-Value Observed: 0.148 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.2α = 90
b = 60.02β = 90
c = 67γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
Aimlessdata 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: 2014-04-02
    Type: Initial release
  • Version 1.1: 2014-04-16
    Changes: Database references
  • Version 1.2: 2018-01-24
    Changes: Structure summary
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description