7UY3

Crystal structure of human Fgr tyrosine kinase in complex with TL02-59

Summary for 7UY3

• Entry DOI: 10.2210/pdb7uy3/pdb
• Descriptor: Tyrosine-protein kinase Fgr, 3-[(6,7-dimethoxyquinazolin-4-yl)oxy]-N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methylbenzamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: fgr, tl02-59, signaling protein, kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 53195.00

Authors

Du, S.,Alvarado, J.J.,Smithgall, T.E. (deposition date: 2022-05-06, release date: 2022-12-28, Last modification date: 2024-10-23)

Primary citation

Du, S.,Alvarado, J.J.,Wales, T.E.,Moroco, J.A.,Engen, J.R.,Smithgall, T.E.
ATP-site inhibitors induce unique conformations of the acute myeloid leukemia-associated Src-family kinase, Fgr.
Structure, 30:1508-1517.e3, 2022

PubMed Abstract: The Src-family kinase Fgr is expressed primarily in myeloid hematopoietic cells and contributes to myeloid leukemia. Here, we present X-ray crystal structures of Fgr bound to the ATP-site inhibitors A-419259 and TL02-59, which show promise as anti-leukemic agents. A-419259 induces a closed Fgr conformation, with the SH3 and SH2 domains engaging the SH2-kinase linker and C-terminal tail, respectively. In the Fgr:A-419259 complex, the activation loop of one monomer inserts into the active site of the other, providing a snapshot of trans-autophosphorylation. By contrast, TL02-59 binding induced SH2 domain displacement from the C-terminal tail and SH3 domain release from the linker. Solution studies using HDX MS were consistent with the crystal structures, with A-419259 reducing and TL02-59 enhancing solvent exposure of the SH3 domain. These structures demonstrate that allosteric connections between the kinase and regulatory domains of Src-family kinases are regulated by the ligand bound to the active site.

PubMed: 36115344
DOI: 10.1016/j.str.2022.08.008

Experimental method

X-RAY DIFFRACTION (2.99 Å)