O naší skupině
Výzkumný program skupiny je zaměřen na biologické membrány a enzymatickou katalýzu v jejich kontextu. Studujeme všudypřítomné intramembránové proteasy z rodiny rhomboidů a mechanistické aspekty jejich funkcí, které jsou relevantní pro biologickou signalizaci, biogenezi membránových proteinů a jejich proteostázi. Při naší práci integrujeme nástroje a přístupy membránové biochemie, enzymologie a strukturní biologie, abychom zjistili jak rhomboidy rozpoznávají své substráty, a uplatňujeme metody kvantitativní proteomiky, buněčné biologie a genetiky, abychom odhalili funkce rhomboidů v organismech. Jsme mezinárodní výzkumná skupina a vítáme motivované studenty a postdoky, kteří by měli zájem s námi pracovat. Neváhejte se ozvat.
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Všechny publikace
General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases
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
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
Scientific Reports 7 : 7283 (2017).
Substrate binding and specificity of rhomboid intramembrane protease revealed by substrate-peptide complex structures
EMBO Journal 33 (20): 2408-2421 (2014).
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