4RT7

Crystal Structure of FLT3 with a small molecule inhibitor

4RT7 の概要

• エントリーDOI: 10.2210/pdb4rt7/pdb
• 分子名称: Receptor-type tyrosine-protein kinase FLT3, 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-(4-{7-[2-(morpholin-4-yl)ethoxy]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea (3 entities in total)
• 機能のキーワード: kinase, transferase, transferase inhibitor, complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P36888
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 48760.98

構造登録者

Zhang, Y.,Zhang, C. (登録日: 2014-11-13, 公開日: 2015-04-22, 最終更新日: 2024-11-06)

主引用文献

Smith, C.C.,Zhang, C.,Lin, K.C.,Lasater, E.A.,Zhang, Y.,Massi, E.,Damon, L.E.,Pendleton, M.,Bashir, A.,Sebra, R.,Perl, A.,Kasarskis, A.,Shellooe, R.,Tsang, G.,Carias, H.,Powell, B.,Burton, E.A.,Matusow, B.,Zhang, J.,Spevak, W.,Ibrahim, P.N.,Le, M.H.,Hsu, H.H.,Habets, G.,West, B.L.,Bollag, G.,Shah, N.P.
Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397.
Cancer Discov, 5:668-679, 2015

PubMed Abstract: Tyrosine kinase domain mutations are a common cause of acquired clinical resistance to tyrosine kinase inhibitors (TKI) used to treat cancer, including the FLT3 inhibitor quizartinib. Mutation of kinase "gatekeeper" residues, which control access to an allosteric pocket adjacent to the ATP-binding site, has been frequently implicated in TKI resistance. The molecular underpinnings of gatekeeper mutation-mediated resistance are incompletely understood. We report the first cocrystal structure of FLT3 with the TKI quizartinib, which demonstrates that quizartinib binding relies on essential edge-to-face aromatic interactions with the gatekeeper F691 residue, and F830 within the highly conserved Asp-Phe-Gly motif in the activation loop. This reliance makes quizartinib critically vulnerable to gatekeeper and activation loop substitutions while minimizing the impact of mutations elsewhere. Moreover, we identify PLX3397, a novel FLT3 inhibitor that retains activity against the F691L mutant due to a binding mode that depends less vitally on specific interactions with the gatekeeper position.

PubMed: 25847190
DOI: 10.1158/2159-8290.CD-15-0060

実験手法

X-RAY DIFFRACTION (3.1 Å)