2HIW

Crystal Structure of Inactive Conformation Abl Kinase Catalytic Domain Complexed with Type II Inhibitor

Summary for 2HIW

• Entry DOI: 10.2210/pdb2hiw/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase ABL1, 7-AMINO-1-METHYL-3-(2-METHYL-5-{[3-(TRIFLUOROMETHYL)BENZOYL]AMINO}PHENYL)-2-OXO-2,3-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-1-IUM (3 entities in total)
• Functional Keywords: kinase domain, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton. Isoform IB: Nucleus membrane; Lipid-anchor: P00519
• Total number of polymer chains: 2
• Total formula weight: 67278.69

Authors

Lee, C. (deposition date: 2006-06-29, release date: 2006-08-22, Last modification date: 2023-08-30)

Primary citation

Okram, B.,Nagle, A.,Adrian, F.J.,Lee, C.,Ren, P.,Wang, X.,Sim, T.,Xie, Y.,Wang, X.,Xia, G.,Spraggon, G.,Warmuth, M.,Liu, Y.,Gray, N.S.
A general strategy for creating
Chem.Biol., 13:779-786, 2006

PubMed Abstract: Kinase inhibitors that bind to the ATP cleft can be broadly classified into two groups: those that bind exclusively to the ATP site with the kinase assuming a conformation otherwise conducive to phosphotransfer (type I), and those that exploit a hydrophobic site immediately adjacent to the ATP pocket made accessible by a conformational rearrangement of the activation loop (type II). To date, all type II inhibitors were discovered by using structure-activity-guided optimization strategies. Here, we describe a general pharmacophore model of type II inhibition that enables a rational "hybrid-design" approach whereby a 3-trifluoromethylbenzamide functionality is appended to four distinct type I scaffolds in order to convert them into their corresponding type II counterparts. We demonstrate that the designed compounds function as type II inhibitors by using biochemical and cellular kinase assays and by cocrystallography with Abl.

PubMed: 16873026
DOI: 10.1016/j.chembiol.2006.05.015

Experimental method

X-RAY DIFFRACTION (2.2 Å)