6ne7

Structure of G810A mutant of RET protein tyrosine kinase domain.

spinqualitylabelsall models 6ne7, resolution 1.99Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ne7 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 1.99Å Ligands: AMP, FMT, PTR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed RET is a transmembrane growth factor receptor. Aberrantly activated RET is found in several types of human cancer and is a target for treating RET aberration-associated cancer. Multiple clinically relevant RET protein tyrosine kinase inhibitors (TKIs) have been identified, but how TKIs bind to RET is unknown except for vandetanib. Nintedanib is a RET TKI that inhibits the vandetanib-resistant RET(G810A) mutant. Here, we determined the X-ray co-crystal structure of RET kinase domain-nintedanib complex to 1.87-A resolution and a RET(G810A) kinase domain crystal structure to 1.99-A resolution. We also identified a vandetanib-resistant RET(L881V) mutation previously found in familial medullary thyroid carcinoma (FMTC). Drug sensitivity profiling of RET(L881V) revealed that it remains sensitive to nintedanib. The RET-nintedanib co-crystal structure disclosed that Leu-730 in RET engages in hydrophobic interactions with the piperazine, anilino, and phenyl groups of nintedanib, providing a structural basis for explaining that the p.L730V mutation identified in nine independently isolated cell lines resistant to nintedanib. Comparisons of RET-nintedanib, RET(G810A), and RET-vandetanib crystal structures suggested that the solvent-front Ala-810 makes hydrophobic contacts with a methyl group and aniline in nintedanib, and blocks water access to two oxygen atoms of vandetanib, resulting in an energetic penalty for burying polar groups. Of note, even though the p.L881V mutation did not affect sensitivity to nintedanib, RET(L881V) was resistant to nintedanib analogs lacking a phenyl group. These results provide structural insights into resistance of RET mutants against the TKIs nintedanib and vandetanib. Structural basis of resistance of mutant RET protein tyrosine kinase to its inhibitors nintedanib and vandetanib.,Terzyan SS, Shen T, Liu X, Huang Q, Teng P, Zhou M, Hilberg F, Cai J, Mooers BHM, Wu J J Biol Chem. 2019 May 22. pii: RA119.007682. doi: 10.1074/jbc.RA119.007682. PMID:31118272 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine kinase receptor 3D structures

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