5FLF

DISEASE LINKED MUTATION IN FGFR

5FLF の概要

• エントリーDOI: 10.2210/pdb5flf/pdb
• 分子名称: FIBROBLAST GROWTH FACTOR RECEPTOR 1, SULFATE ION, ACETATE ION, ... (6 entities in total)
• 機能のキーワード: transferase, auto-activating, cancer, growth factor, receptor, mutation
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein: P11362
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 177743.93

構造登録者

Thiyagarajan, N.,Bunney, T.D.,Katan, M. (登録日: 2015-10-26, 公開日: 2016-03-30, 最終更新日: 2024-01-10)

主引用文献

Patani, H.,Bunney, T.D.,Thiyagarajan, N.,Norman, R.A.,Ogg, D.,Breed, J.,Ashford, P.,Potterton, A.,Edwards, M.,Williams, S.V.,Thomson, G.S.,Pang, C.S.,Knowles, M.A.,Breeze, A.L.,Orengo, C.,Phillips, C.,Katan, M.
Landscape of Activating Cancer Mutations in Fgfr Kinases and Their Differential Responses to Inhibitors in Clinical Use.
Oncotarget, 7:24252-, 2016

PubMed Abstract: Frequent genetic alterations discovered in FGFRs and evidence implicating some as drivers in diverse tumors has been accompanied by rapid progress in targeting FGFRs for anticancer treatments. Wider assessment of the impact of genetic changes on the activation state and drug responses is needed to better link the genomic data and treatment options. We here apply a direct comparative and comprehensive analysis of FGFR3 kinase domain variants representing the diversity of point-mutations reported in this domain. We reinforce the importance of N540K and K650E and establish that not all highly activating mutations (for example R669G) occur at high-frequency and conversely, that some "hotspots" may not be linked to activation. Further structural characterization consolidates a mechanistic view of FGFR kinase activation and extends insights into drug binding. Importantly, using several inhibitors of particular clinical interest (AZD4547, BGJ-398, TKI258, JNJ42756493 and AP24534), we find that some activating mutations (including different replacements of the same residue) result in distinct changes in their efficacy. Considering that there is no approved inhibitor for anticancer treatments based on FGFR-targeting, this information will be immediately translatable to ongoing clinical trials.

PubMed: 26992226
DOI: 10.18632/ONCOTARGET.8132

実験手法

X-RAY DIFFRACTION (2.58 Å)