4RT7

Crystal Structure of FLT3 with a small molecule inhibitor

Summary for 4RT7

• Entry DOI: 10.2210/pdb4rt7/pdb
• Descriptor: 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)
• Functional Keywords: kinase, transferase, transferase inhibitor, complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P36888
• Total number of polymer chains: 1
• Total formula weight: 48760.98

Authors

Zhang, Y.,Zhang, C. (deposition date: 2014-11-13, release date: 2015-04-22, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.1 Å)