6fek

Oncogenic point mutation of RET receptor tyrosine kinase

spinqualitylabelsall models 6fek, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6fek is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: ADN, FMT, PTR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. A secondary RET mutation in the activation loop conferring resistance to vandetanib.,Nakaoku T, Kohno T, Araki M, Niho S, Chauhan R, Knowles PP, Tsuchihara K, Matsumoto S, Shimada Y, Mimaki S, Ishii G, Ichikawa H, Nagatoishi S, Tsumoto K, Okuno Y, Yoh K, McDonald NQ, Goto K Nat Commun. 2018 Feb 12;9(1):625. doi: 10.1038/s41467-018-02994-7. PMID:29434222 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cadherin 3D structures Tyrosine kinase receptor 3D structures

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