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- W2791768052 abstract "We have developed a cell-based high-throughput screening (HTS) method using time-resolved fluorescence energy transfer (TR-FRET) sensitive to binding and structural dynamics of the SERCA2a/PLB complex. Overwhelming evidence establishes the membrane protein complex between the sarcoplasmic reticulum Ca-ATPase 2a (SERCA2a) and its regulator phospholamban (PLB) as a therapeutic target for reversing cardiac contractile dysfunction caused by aberrant calcium handling. Unfortunately, efforts to discover compounds with specificity for this complex have yet to yield an efficacious drug. GFP-SERCA2a (donor) was co-expressed in the endoplasmic reticulum of HEK293 cells with and without RFP-PLB (acceptor), and FRET was measured in a fluorescence lifetime microplate reader. We carried out a triplicate screen against a small chemical library (LOPAC) and identified 21 compounds that reproducibly changed FRET by >3 SD. Dose-response of FRET and ATPase activity readouts reveal that ten hits reproducibly alter SERCA2a/PLB structure and function. One compound increases SERCA2a Ca affinity and activity (EC50 = 23 µM) at physiological calcium levels in cardiac SR, but not in skeletal SR, suggesting that the compound is acting specifically on the SERCA2a/PLB complex. These properties characterize a drug that could reverse calcium mishandling. The excellent Z’ factor and correlation between structural and functional assays validate this method to discover SERCA2a-PLB complex effectors for large-scale HTS campaigns. This work was supported by NIH grants (GM27906, HL129814, AR07612, and DA037622)." @default.
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- W2791768052 date "2018-02-01" @default.
- W2791768052 modified "2023-10-18" @default.
- W2791768052 title "Discovery of SERCA2a/PLB Activators and Inhibitors by Structure-Based High-throughput Screening using Live Cell FRET Biosensors" @default.
- W2791768052 doi "https://doi.org/10.1016/j.bpj.2017.11.827" @default.
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