6FEK

Oncogenic point mutation of RET receptor tyrosine kinase

6FEK の概要

• エントリーDOI: 10.2210/pdb6fek/pdb
• 分子名称: Proto-oncogene tyrosine-protein kinase receptor Ret, FORMIC ACID, ADENOSINE, ... (4 entities in total)
• 機能のキーワード: tyrosine kinase, oncogene, mutation, oncoprotein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane ; Single-pass type I membrane protein : P07949
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34711.00

構造登録者

McDonald, N.Q.,Kohno, T. (登録日: 2018-01-02, 公開日: 2018-02-28, 最終更新日: 2024-10-16)

主引用文献

Nakaoku, T.,Kohno, T.,Araki, M.,Niho, S.,Chauhan, R.,Knowles, P.P.,Tsuchihara, K.,Matsumoto, S.,Shimada, Y.,Mimaki, S.,Ishii, G.,Ichikawa, H.,Nagatoishi, S.,Tsumoto, K.,Okuno, Y.,Yoh, K.,McDonald, N.Q.,Goto, K.
A secondary RET mutation in the activation loop conferring resistance to vandetanib.
Nat Commun, 9:625-625, 2018

PubMed Abstract: Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects.

PubMed: 29434222
DOI: 10.1038/s41467-018-02994-7

実験手法

X-RAY DIFFRACTION (2.3 Å)