3UE4

Structural and spectroscopic analysis of the kinase inhibitor bosutinib binding to the Abl tyrosine kinase domain

Summary for 3UE4

• Entry DOI: 10.2210/pdb3ue4/pdb
• Descriptor: Tyrosine-protein kinase ABL1, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile (3 entities in total)
• Functional Keywords: protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 67506.87

Authors

Boxer, S.G.,Levinson, N.M. (deposition date: 2011-10-28, release date: 2012-04-18, Last modification date: 2024-02-28)

Primary citation

Levinson, N.M.,Boxer, S.G.
Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the abl tyrosine kinase domain.
Plos One, 7:e29828-e29828, 2012

PubMed Abstract: Chronic myeloid leukemia (CML) is caused by the kinase activity of the BCR-Abl fusion protein. The Abl inhibitors imatinib, nilotinib and dasatinib are currently used to treat CML, but resistance to these inhibitors is a significant clinical problem. The kinase inhibitor bosutinib has shown efficacy in clinical trials for imatinib-resistant CML, but its binding mode is unknown. We present the 2.4 Å structure of bosutinib bound to the kinase domain of Abl, which explains the inhibitor's activity against several imatinib-resistant mutants, and reveals that similar inhibitors that lack a nitrile moiety could be effective against the common T315I mutant. We also report that two distinct chemical compounds are currently being sold under the name "bosutinib", and report spectroscopic and structural characterizations of both. We show that the fluorescence properties of these compounds allow inhibitor binding to be measured quantitatively, and that the infrared absorption of the nitrile group reveals a different electrostatic environment in the conserved ATP-binding sites of Abl and Src kinases. Exploiting such differences could lead to inhibitors with improved selectivity.

PubMed: 22493660
DOI: 10.1371/journal.pone.0029828

Experimental method

X-RAY DIFFRACTION (2.424 Å)