3PYY

Discovery and Characterization of a Cell-Permeable, Small-molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site

Summary for 3PYY

• Entry DOI: 10.2210/pdb3pyy/pdb
• Descriptor: Tyrosine-protein kinase ABL1, SULFATE ION, 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE, ... (7 entities in total)
• Functional Keywords: tyrosine kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 71871.75

Authors

Yang, J.,Campobasso, N.,Biju, M.P.,Fisher, K.,Pan, X.Q.,Cottom, J.,Galbraith, S.,Ho, T.,Zhang, H.,Hong, X.,Ward, P.,Hofmann, G.,Siegfried, B. (deposition date: 2010-12-13, release date: 2011-03-09, Last modification date: 2025-05-07)

Primary citation

Yang, J.,Campobasso, N.,Biju, M.P.,Fisher, K.,Pan, X.Q.,Cottom, J.,Galbraith, S.,Ho, T.,Zhang, H.,Hong, X.,Ward, P.,Hofmann, G.,Siegfried, B.,Zappacosta, F.,Washio, Y.,Cao, P.,Qu, J.,Bertrand, S.,Wang, D.Y.,Head, M.S.,Li, H.,Moores, S.,Lai, Z.,Johanson, K.,Burton, G.,Erickson-Miller, C.,Simpson, G.,Tummino, P.,Copeland, R.A.,Oliff, A.
Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site.
Chem.Biol., 18:177-186, 2011

PubMed Abstract: c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

PubMed: 21338916
DOI: 10.1016/j.chembiol.2010.12.013

Experimental method

X-RAY DIFFRACTION (1.85 Å)