Lecture 'Translating N-Terminomics Data: A Pharmacologic Molecular Corrector
 Rescues Mutant MALT1 Paracaspase Activity and NFkB Activation in a Patient Suffering from
 Combined Immunodeficiency'

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Students, Employees, Alumni, Business
23-04-2018 from 11:30 to 12:45
UGent-VIB-onderzoeksgebouw, Technologiepark 927, 9052 Zwijnaarde
VIB-UGent Center for Inflammation Research (GE01/WE14/WE10)
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Christopher Overall (University of British Columbia, Vancouver) will explain how a small molecule rescues deficient MALT1 protease activity in men.

Uncontrolled and upregulated proteases are attractive drug targets in a variety of malignancies, inflammatory and autoimmune diseases. However, increasing protease activity to correct delayed or insufficient protease expression or activity in disease is chemically and therapeutically challenging.

MALT1 is central for transducing lymphocyte antigen receptor activation of NFκB. We discovered allosteric inhibitors of MALT1 paracaspase activity that bind by replacing the side chain of Trp580 and locking the protease in an inactive conformation.

Interestingly, we had previously identified a patient homozygous for a hypomorphic MALT1 mutation at Trp580 (tryptophan to serine) who suffered from combined immunodeficiency. Here we show that a low molecular weight pharmacological corrector compound rescued protease deficiency by substituting for the mutated residue to restore function and increase cleavage activity, inspiring potential precision therapies to increase mutant enzyme activity.