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Journal Article

Closantel is an allosteric inhibitor of human Taspase1


Langer,  Julian David       
Proteomics and Mass Spectrometry, Max Planck Institute of Biophysics, Max Planck Society;

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Luciano, V., Proschak, E., Langer, J. D., Knapp, S., Heering, J., & Marschalek, R. (2021). Closantel is an allosteric inhibitor of human Taspase1. iScience, 24(12): e103524. doi:10.1016/j.isci.2021.103524.

Cite as: https://hdl.handle.net/21.11116/0000-0009-B0E7-B
Dimerization of Taspase1 activates an intrinsic serine protease function that leads to the catalytic Thr234 residue, which allows to catalyze the consensus sequence Q-3X-2D-1⋅G1X2D3D4, present in Trithorax family members and TFIIA. Noteworthy, Taspase1 performs only a single hydrolytic step on substrate proteins, which makes it impossible to screen for inhibitors in a classical screening approach. Here, we report the development of an HTRF reporter assay that allowed the identification of an inhibitor, Closantel sodium, that inhibits Taspase1 in a noncovalent fashion (IC50 = 1.6 μM). The novel inhibitor interferes with the dimerization step and/or the intrinsic serine protease function of the proenzyme. Of interest, Taspase1 is required to activate the oncogenic functions of the leukemogenic AF4-MLL fusion protein and was shown in several studies to be overexpressed in many solid tumors. Therefore, the inhibitor may be useful for further validation of Taspase1 as a target for cancer therapy.