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- Title
Structural Effects of Fusicoccin upon Upregulation of 14‐3‐3‐Phospholigand Interaction and Cytotoxic Activity.
- Authors
Ohkanda, Junko; Kusumoto, Atsushi; Punzalan, Louvy; Masuda, Ryoma; Wang, Chenyu; Parvatkar, Prakash; Akase, Dai; Aida, Misako; Uesugi, Motonari; Higuchi, Yusuke; Kato, Nobuo
- Abstract
Fusicoccins (FCs) exhibit various cellular activities in mammalian cells, but details of the mechanism of action are not fully understood. In this study, we synthesized two pairs of model derivatives of FCs differing only in the presence and absence of a 12‐hydroxyl group and evaluated their binding to a 14‐3‐3 protein together with various mode 1 and mode 3 phosphopeptide ligands. Our results demonstrate that the 12‐hydroxyl group hampers binding to 14‐3‐3 with mode 1 phospholigands, presumably due to steric repulsion with the i+2 residue. Furthermore, cell‐based evaluations showed that only non‐substituted FCs exhibit significant cytotoxicity and all 12‐hydroxyl derivatives were inactive, demonstrating a clear correlation with their ability to form ternary complexes with 14‐3‐3 and a mode 1 ligand. These results suggest that binding to 14‐3‐3 and a partner protein(s) possessing a mode 1 sequence plays a role in the mechanism of action of 12‐non‐substituted FCs. OH is crucial: Semi‐synthetic fusicoccin derivatives were evaluated for their binding to a 14‐3‐3 protein and phosphopeptide libraries, and for their antiproliferative activity. The results demonstrated that the 12‐hydroxyl group determines their selectivity for mode 3 phospholigands upon 14‐3‐3‐complex formation (see figure).
- Subjects
FUSICOCCIN; LIGANDS (Chemistry); CYTOTOXIC T cells; CELL-mediated cytotoxicity; HYDROXYL group analysis; STERIC hindrance
- Publication
Chemistry - A European Journal, 2018, Vol 24, Issue 60, p16066
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201804428