Blockage of Store-Operated Ca 2+ Influx by Synta66 is Mediated by Direct Inhibition of the Ca 2+ Selective Orai1 Pore.

Autor: Waldherr L; Gottfried Schatz Research Centre, Medical University of Graz, A-8010 Graz, Austria., Tiffner A; Institute of Biophysics, JKU Life Science Centre, Johannes Kepler University Linz, A-4020 Linz, Austria., Mishra D; Centre for Nanobiology and Structural Biology, Academy of Sciences of the Czech Republic, 373 33 Nové Hrady, Czech Republic., Sallinger M; Institute of Biophysics, JKU Life Science Centre, Johannes Kepler University Linz, A-4020 Linz, Austria., Schober R; Gottfried Schatz Research Centre, Medical University of Graz, A-8010 Graz, Austria.; Institute of Biophysics, JKU Life Science Centre, Johannes Kepler University Linz, A-4020 Linz, Austria., Frischauf I; Institute of Biophysics, JKU Life Science Centre, Johannes Kepler University Linz, A-4020 Linz, Austria., Schmidt T; Gottfried Schatz Research Centre, Medical University of Graz, A-8010 Graz, Austria., Handl V; Department of Neurosurgery, Medical University of Graz, A-8010 Graz, Austria., Sagmeister P; Institute of Chemistry, University of Graz, Heinrichstraße 28, A-8010 Graz, Austria., Köckinger M; Institute of Chemistry, University of Graz, Heinrichstraße 28, A-8010 Graz, Austria., Derler I; Institute of Biophysics, JKU Life Science Centre, Johannes Kepler University Linz, A-4020 Linz, Austria., Üçal M; Department of Neurosurgery, Medical University of Graz, A-8010 Graz, Austria., Bonhenry D; Centre for Nanobiology and Structural Biology, Academy of Sciences of the Czech Republic, 373 33 Nové Hrady, Czech Republic., Patz S; Department of Neurosurgery, Medical University of Graz, A-8010 Graz, Austria., Schindl R; Gottfried Schatz Research Centre, Medical University of Graz, A-8010 Graz, Austria.; Institute of Biophysics, JKU Life Science Centre, Johannes Kepler University Linz, A-4020 Linz, Austria.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2020 Oct 06; Vol. 12 (10). Date of Electronic Publication: 2020 Oct 06.
DOI: 10.3390/cancers12102876
Abstrakt: The Ca 2+ sensor STIM1 and the Ca 2+ channel Orai1 that form the store-operated Ca 2+ (SOC) channel complex are key targets for drug development. Selective SOC inhibitors are currently undergoing clinical evaluation for the treatment of auto-immune and inflammatory responses and are also deemed promising anti-neoplastic agents since SOC channels are linked with enhanced cancer cell progression. Here, we describe an investigation of the site of binding of the selective inhibitor Synta66 to the SOC channel Orai1 using docking and molecular dynamics simulations, and live cell recordings. Synta66 binding was localized to the extracellular site close to the transmembrane (TM)1 and TM3 helices and the extracellular loop segments, which, importantly, are adjacent to the Orai1-selectivity filter. Synta66-sensitivity of the Orai1 pore was, in fact, diminished by both Orai1 mutations affecting Ca 2+ selectivity and permeation of Na + in the absence of Ca 2+ . Synta66 also efficiently blocked SOC in three glioblastoma cell lines but failed to interfere with cell viability, division and migration. These experiments provide new structural and functional insights into selective drug inhibition of the Orai1 Ca 2+ channel by a high-affinity pore blocker.
Databáze: MEDLINE
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