6SEQ

Lemur tyrosine kinase 3 (LMTK3)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.198 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

The structure-function relationship of oncogenic LMTK3.

Ditsiou, A.Cilibrasi, C.Simigdala, N.Papakyriakou, A.Milton-Harris, L.Vella, V.Nettleship, J.E.Lo, J.H.Soni, S.Smbatyan, G.Ntavelou, P.Gagliano, T.Iachini, M.C.Khurshid, S.Simon, T.Zhou, L.Hassell-Hart, S.Carter, P.Pearl, L.H.Owen, R.L.Owens, R.J.Roe, S.M.Chayen, N.E.Lenz, H.J.Spencer, J.Prodromou, C.Klinakis, A.Stebbing, J.Giamas, G.

(2020) Sci Adv 6

  • DOI: https://doi.org/10.1126/sciadv.abc3099
  • Primary Citation of Related Structures:  
    6SEQ

  • PubMed Abstract: 

    Elucidating signaling driven by lemur tyrosine kinase 3 (LMTK3) could help drug development. Here, we solve the crystal structure of LMTK3 kinase domain to 2.1Å resolution, determine its consensus motif and phosphoproteome, unveiling in vitro and in vivo LMTK3 substrates. Via high-throughput homogeneous time-resolved fluorescence screen coupled with biochemical, cellular, and biophysical assays, we identify a potent LMTK3 small-molecule inhibitor (C28). Functional and mechanistic studies reveal LMTK3 is a heat shock protein 90 (HSP90) client protein, requiring HSP90 for folding and stability, while C28 promotes proteasome-mediated degradation of LMTK3. Pharmacologic inhibition of LMTK3 decreases proliferation of cancer cell lines in the NCI-60 panel, with a concomitant increase in apoptosis in breast cancer cells, recapitulating effects of LMTK3 gene silencing. Furthermore, LMTK3 inhibition reduces growth of xenograft and transgenic breast cancer mouse models without displaying systemic toxicity at effective doses. Our data reinforce LMTK3 as a druggable target for cancer therapy.


  • Organizational Affiliation

    Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase LMTK31,460Homo sapiensMutation(s): 0 
Gene Names: LMTK3KIAA1883TYKLM3
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q96Q04 (Homo sapiens)
Explore Q96Q04 
Go to UniProtKB:  Q96Q04
PHAROS:  Q96Q04
GTEx:  ENSG00000142235 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ96Q04
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.198 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.586α = 90
b = 63.999β = 90
c = 134.672γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
PDB_EXTRACTdata extraction
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Other privateUnited KingdomG1828

Revision History  (Full details and data files)

  • Version 1.0: 2020-11-25
    Type: Initial release
  • Version 1.1: 2024-05-15
    Changes: Data collection, Database references