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Instruments / Technical Area	Publication Details	Published	Actions
I24-Microfocus Macromolecular Crystallography	The structure-function relationship of oncogenic LMTK3 Angeliki Ditsiou , Chiara Cilibrasi , Nikiana Simigdala , Athanasios Papakyriakou , Leanne Milton-Harris , Viviana Vella , Joanne E. Nettleship , Jae Ho Lo , Shivani Soni , Goar Smbatyan , Panagiota Ntavelou , Teresa Gagliano , Maria Chiara Iachini , Sahir Khurshid , Thomas Simon , Lihong Zhou , Storm Hassell-Hart , Philip Carter , Laurence H. Pearl , Robin L. Owen , Raymond J. Owens , S. Mark Roe , Naomi E. Chayen , Heinz-Josef Lenz , John Spencer , Chrisostomos Prodromou , Apostolos Klinakis , Justin Stebbing , Georgios Giamas Science Advances 6 DOI: 10.1126/sciadv.abc3099 Diamond Proposal Number(s): [14493] Open Access Show Abstract ▼ 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.	Nov 2020

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I24-Microfocus Macromolecular Crystallography

The structure-function relationship of oncogenic LMTK3