5MQL

Crystal structure of dCK mutant C3S in complex with masitinib and UDP

5MQL の概要

• エントリーDOI: 10.2210/pdb5mql/pdb
• 分子名称: Deoxycytidine kinase, URIDINE-5'-DIPHOSPHATE, Masitinib, ... (6 entities in total)
• 機能のキーワード: deoxycytidine kinase, dck, masitinib, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P27707
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 138846.76

構造登録者

Rebuffet, E.,Hammam, K.,Saez-Ayala, M.,Gros, L.,Lopez, S.,Hajem, B.,Humbert, M.,Baudelet, E.,Audebert, S.,Betzi, S.,Lugari, A.,Combes, S.,Pez, D.,Letard, S.,Mansfield, C.,Moussy, A.,de Sepulveda, P.,Morelli, X.,Dubreuil, P. (登録日: 2016-12-20, 公開日: 2017-11-22, 最終更新日: 2024-01-17)

主引用文献

Hammam, K.,Saez-Ayala, M.,Rebuffet, E.,Gros, L.,Lopez, S.,Hajem, B.,Humbert, M.,Baudelet, E.,Audebert, S.,Betzi, S.,Lugari, A.,Combes, S.,Letard, S.,Casteran, N.,Mansfield, C.,Moussy, A.,De Sepulveda, P.,Morelli, X.,Dubreuil, P.
Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology.
Nat Commun, 8:1420-1420, 2017

PubMed Abstract: Masitinib, a highly selective protein kinase inhibitor, can sensitise gemcitabine-refractory cancer cell lines when used in combination with gemcitabine. Here we report a reverse proteomic approach that identifies the target responsible for this sensitisation: the deoxycytidine kinase (dCK). Masitinib, as well as other protein kinase inhibitors, such as imatinib, interact with dCK and provoke an unforeseen conformational-dependent activation of this nucleoside kinase, modulating phosphorylation of nucleoside analogue drugs. This phenomenon leads to an increase of prodrug phosphorylation of most of the chemotherapeutic drugs activated by this nucleoside kinase. The unforeseen dual activity of protein kinase inhibition/nucleoside kinase activation could be of great therapeutic benefit, through either reducing toxicity of therapeutic agents by maintaining effectiveness at lower doses or by counteracting drug resistance initiated via down modulation of dCK target.

PubMed: 29127277
DOI: 10.1038/s41467-017-01582-5

実験手法

X-RAY DIFFRACTION (3.25 Å)