Open AccessDisruption of endocytosis through chemical inhibition of clathrin heavy chain function
Author(s) -
Wim Dejonghe,
Isha Sharma,
Bram Denoo,
Steven De Munck,
Qing Lü,
Kiril Mishev,
Haydar Bulut,
Evelien Mylle,
Riet De Rycke,
Mina Vasileva,
Daniel V. Savatin,
Wim Nerinckx,
An Staes,
Andrzej Drozdzecki,
Dominique Audenaert,
Klaas Yperman,
Annemieke Madder,
Jiřı́ Friml,
Daniël Van Damme,
Kris Gevaert,
Volker Haucke,
Savvas N. Savvides,
Johan M. Winne,
Eugenia Russinova
Publication year - 2019
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-019-0262-1
Subject(s) - clathrin , endocytosis , function (biology) , chemical biology , microbiology and biotechnology , chemistry , small molecule , computational biology , biochemistry , biology , biophysics , receptor
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.