6E4L

The structure of the N-terminal domain of human clathrin heavy chain 1 (nTD) in complex with ES9

Summary for 6E4L

• Entry DOI: 10.2210/pdb6e4l/pdb
• Descriptor: Clathrin heavy chain 1, DIMETHYL SULFOXIDE, GLYCEROL, ... (7 entities in total)
• Functional Keywords: clathrin-mediated endocytosis (cme), clathrin n-terminal domain (ntd), chemical inhibition, endocytosis
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 41973.87

Authors

Dejonghe, W.,Sharma, I.,Denoo, B.,Munck, S.D.,Bulut, H.,Mylle, E.,Vasileva, M.,Lu, Q.,Savatin, D.V.,Mishev, K.,Nerinckx, W.,Staes, A.,Drozdzecki, A.,Audenaert, D.,Madder, A.,Friml, J.,Damme, D.V.,Gevaert, K.,Haucke, V.,Savvides, S.,Winne, J.,Russinova, E. (deposition date: 2018-07-17, release date: 2019-04-24, Last modification date: 2023-10-11)

Primary citation

Dejonghe, W.,Sharma, I.,Denoo, B.,De Munck, S.,Lu, Q.,Mishev, K.,Bulut, H.,Mylle, E.,De Rycke, R.,Vasileva, M.,Savatin, D.V.,Nerinckx, W.,Staes, A.,Drozdzecki, A.,Audenaert, D.,Yperman, K.,Madder, A.,Friml, J.,Van Damme, D.,Gevaert, K.,Haucke, V.,Savvides, S.N.,Winne, J.,Russinova, E.
Disruption of endocytosis through chemical inhibition of clathrin heavy chain function.
Nat.Chem.Biol., 15:641-649, 2019

PubMed Abstract: 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.

PubMed: 31011214
DOI: 10.1038/s41589-019-0262-1

Experimental method

X-RAY DIFFRACTION (1.6 Å)