Thermal Shift: Destabilization could also be an Outcome
In their report “Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay” (5 July, p. 84) D. M. Molina et al. describe a novel assay that takes advantage of increased thermostability of proteins upon ligand binding in intact cells. Noteworthy, formation of a protein-ligand complex in a simple solution might result in an increased thermostability for some protein-ligand pairs, but on contrary might have destabilizing effect for others. A thermodynamic model has been described that explains this two experimentally observed possibilities with a preferential ligand binding to the native (more stable) protein confirmation or to unfolded (less stable) protein state, respectively . Adding additional level of complexity in the context of the novel intact cell-based assay developed by Molina et al., ligand binding-induced protein degradation, as described for example for the nuclear receptors RXR  and PPARgamma , is an often observed phenomena likely constituting a physiologically relevant negative-feedback regulation mechanism aiming to eliminate some receptor proteins immediately after the ligand-induced signalling has been initiated. Last but not least, since Molina et al. recommend the newly developed method as a tool for drug discovery, it should be pointed that in cases when particular protein target needs to be blocked it could be of advantage to discover ligands that are having destabilizeing rather than stabilizing effect on this protein target. The benefit from such selective protein target-destabilizing action is for example demonstrated from ICI-182,780 (Faslodex), a dual action estrogen receptor antagonist and destabilizer used for breast cancer treatment .
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