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IOCB Prague

Kvido Stříšovský Group

Intramembrane Proteolysis and Biological Regulation
Research Group
Junior
BIO cluster

About our group

The research in Strisovsky lab is focused on biological membranes and enzymatic catalysis occurring in their context. We are studying the ubiquitous intramembrane proteases of the rhomboid family and the mechanistic aspects of their functions relevant for biological signaling, membrane protein biogenesis and homeostasis. In our work we integrate the tools of membrane biochemistry, enzymology and structural biology to understand how rhomboid proteases recognise and select substrates, and employ methods of quantitative proteomics, cell biology and genetics to uncover molecular basis of rhomboid functions in organisms. We are an international group and we are always eager to consider motivated students and postdocs who would like to join us. Just drop us a line.
External group website
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Publications

All publications
General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases
General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases
Anežka Tichá
Stancho Stanchev
K. R. Vinothkumar
David Cameron Mikles
Petr Pachl
Jakub Began
Jan Škerle
Kateřina Švehlová
M. T. N. Nguyen
S. H. L. Verhelst
D. C. Johnson
D. A. Bachovchin
Martin Lepšík
Pavel Majer
Kvido Stříšovský
Cell Chemical Biology 24 (12): 1523-1536 (2017).
Rhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson\'s disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl α-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude. Such peptidyl ketoamides show selectivity for rhomboids, leaving most human serine hydrolases unaffected. Crystal structures show that these compounds bind the active site of rhomboid covalently and in a substrate-like manner, and kinetic analysis reveals their reversible, slow-binding, non-competitive mechanism. Since ketoamides are clinically used pharmacophores, our findings uncover a straightforward modular way for the design of specific inhibitors of rhomboid proteases, which can be widely applicable in cell biology and drug discovery.
The Rhomboid Superfamily: Structural Mechanisms and Chemical Biology Opportunities
Anežka Tichá
Blanka Collis
Kvido Stříšovský
Trends in Biochemical Sciences 43 (9): 726-739 (2018).
Quantitative proteomics screen identifies a substrate repertoire of rhomboid protease RHBDL2 in human cells and implicates it in epithelial homeostasis
Nicholas Johnson
Jana Březinová
E. Stephens
E. Burbridge
M. Freeman
C. Adrain
Kvido Stříšovský
Scientific Reports 7 : 7283 (2017).
Substrate binding and specificity of rhomboid intramembrane protease revealed by substrate-peptide complex structures
Sebastian Zoll
Stancho Stanchev
Jakub Began
Jan Škerle
Martin Lepšík
Lucie Peclinovská
Pavel Majer
Kvido Stříšovský
EMBO Journal 33 (20): 2408-2421 (2014).