6FEK

Oncogenic point mutation of RET receptor tyrosine kinase

Summary for 6FEK

• Entry DOI: 10.2210/pdb6fek/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase receptor Ret, FORMIC ACID, ADENOSINE, ... (4 entities in total)
• Functional Keywords: tyrosine kinase, oncogene, mutation, oncoprotein
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P07949
• Total number of polymer chains: 1
• Total formula weight: 34711.00

Authors

McDonald, N.Q.,Kohno, T. (deposition date: 2018-01-02, release date: 2018-02-28, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)