Disruption of endocytosis through chemical inhibition of clathrin heavy chain function
| Autor: | Eugenia Russinova, Wim Dejonghe, Andrzej Drozdzecki, Daniel Valentin Savatin, An Staes, Kiril Mishev, Volker Haucke, Riet De Rycke, Isha Sharma, Kris Gevaert, Annemieke Madder, Evelien Mylle, Steven De Munck, Bram Denoo, Daniël Van Damme, Johan M. Winne, Klaas Yperman, Wim Nerinckx, Savvas N. Savvides, Haydar Bulut, Jiří Friml, Qing Lu, Mina Vasileva, Dominique Audenaert |
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| Rok vydání: | 2019 |
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Molecular Arabidopsis Thiophenes Endocytosis Clathrin 03 medical and health sciences symbols.namesake Benzene Derivatives Molecule Humans Molecular Biology 030304 developmental biology 0303 health sciences Heavy chain biology Molecular Structure Chemistry 030302 biochemistry & molecular biology Cell Biology Golgi apparatus biology.organism_classification Small molecule Clathrin Heavy Chains biology.protein Biophysics symbols Function (biology) |
| Zdroj: | Nature Chemical Biology |
| ISSN: | 1552-4450 |
| DOI: | 10.1038/s41589-019-0262-1 |
| Popis: | Clathrin-mediated endocytosis (CME) is a highly conserved and essential cellular process in eukaryotic cells, but its dynamic and vital nature makes it challenging to study using classical genetics tools. In contrast, although small molecules can acutely and reversibly perturb CME, the few chemical CME inhibitors that have been applied to plants are either ineffective or show undesirable side effects. Here, we identify the previously described endosidin9 (ES9) as an inhibitor of clathrin heavy chain (CHC) function in both Arabidopsis and human cells through affinity-based target isolation, in vitro binding studies and X-ray crystallography. Moreover, we present a chemically improved ES9 analog, ES9-17, which lacks the undesirable side effects of ES9 while retaining the ability to target CHC. ES9 and ES9-17 have expanded the chemical toolbox used to probe CHC function, and present chemical scaffolds for further design of more specific and potent CHC inhibitors across different systems. |
| Databáze: | OpenAIRE |
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