6SDC

Crystal structure of D1228V cMET bound by foretinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.201 

wwPDB Validation 3D Report Full Report


This is version 1.1 of the entry. See complete history

Literature

Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors.

Collie, G.W.Koh, C.M.O'Neill, D.J.Stubbs, C.J.Khurana, P.Eddershaw, A.Snijder, A.Mauritzson, F.Barlind, L.Dale, I.L.Shaw, J.Phillips, C.Hennessy, E.J.Cheung, T.Narvaez, A.J.

(2019) Acs Med.Chem.Lett. 10: 1322-1327

  • DOI: 10.1021/acsmedchemlett.9b00276
  • Primary Citation of Related Structures:  

  • PubMed Abstract: 
  • Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is n ...

    Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Toward this end, we report here the first crystal structures of the recent clinically observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical, and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase, which could have implications for small molecule inhibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.


    Organizational Affiliation

    Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.,Discovery Sciences, R&D, AstraZeneca, Cambridge, U.K.,Oncology, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.,Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.




Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Hepatocyte growth factor receptor
A
309Homo sapiensMutation(s): 1 
Gene Names: MET
EC: 2.7.10.1
Find proteins for P08581 (Homo sapiens)
Go to Gene View: MET
Go to UniProtKB:  P08581
Small Molecules
Ligands 1 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
88Z
Query on 88Z

Download SDF File 
Download CCD File 
A
N-(3-fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
C34 H34 F2 N4 O6
CXQHYVUVSFXTMY-UHFFFAOYSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.201 
  • Space Group: P 21 21 21
Unit Cell:
Length (Å)Angle (°)
a = 42.574α = 90.00
b = 80.396β = 90.00
c = 91.306γ = 90.00
Software Package:
Software NamePurpose
BUSTERrefinement
DIALSdata scaling
PDB_EXTRACTdata extraction
DIALSdata reduction
PHASERphasing

Structure Validation

View Full Validation Report or Ramachandran Plots



Entry History 

Deposition Data

Revision History 

  • Version 1.0: 2019-08-14
    Type: Initial release
  • Version 1.1: 2019-10-02
    Type: Data collection, Database references