Selective inhibition of calcineurin-NFAT signaling by blocking protein-protein interaction with small organic molecules.
Transient or reversible protein-protein interactions are commonly used to ensure efficient targeting of signaling enzymes to their cellular substrates. These interactions include direct binding to substrate, interaction with an accessory or scaffold protein, and positioning at subcellular locations in proximity to substrates. The existence of specialized targeting mechanisms raises the possibility of designing inhibitors that do not block enzyme activity per se, but rather interfere with targeting of the enzyme to one or more of its substrates within the cell. Here, we identify small organic molecules that specifically block targeting of the protein phosphatase calcineurin to its substrate nuclear factor of activated T cells (NFAT, also termed NFATc) and show that they are effective inhibitors of calcineurin-NFAT signaling.
Roehrl
Michael H A
MH
Department of Biological Chemistry, Harvard Medical School, Boston, MA 02115, USA.
Kang
Sunghyun
S
Aramburu
José
J
Wagner
Gerhard
G
Rao
Anjana
A
Hogan
Patrick G
PG
D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009842:Oligopeptides / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009842:Oligopeptides; D014157:Transcription Factors; C121611:VIVIT peptide; D019703:Calcineurin