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Selective inhibition of calcineurin-NFAT signaling by blocking protein–protein interaction with small organic molecules

By Michael H. A. Roehrl, Sunghyun Kang, José Aramburu, Gerhard Wagner, Anjana Rao and Patrick G. Hogan

Abstract

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

Topics: Biological Sciences
Publisher: National Academy of Sciences
Year: 2004
DOI identifier: 10.1073/pnas.0401835101
OAI identifier: oai:pubmedcentral.nih.gov:419644
Provided by: PubMed Central
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