Journal
INTERNATIONAL JOURNAL OF MASS SPECTROMETRY
Volume 427, Issue -, Pages 151-156Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijms.2017.12.002
Keywords
Ion mobility; Protein kinases; Pharmaceuticals; Collisional activation; Native mass spectrometry
Funding
- National Science Foundation (CAREER) [1253384]
- Rackham Graduate School
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1253384] Funding Source: National Science Foundation
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Chronic myeloid leukemia is caused by a chimeric oncoprotein comprised of the breakpoint cluster region protein and the Abelson protein tyrosine kinase, and is often treated using protein tyrosine kinase inhibitors that target the ATP-binding domain of the kinase. A more recently-discovered class of inhibitors target the myristoylation site in the C-terminal region of the kinase domain, and offer allosteric control over kinase activity. The discovery process surrounding such inhibitors, however, is exceptionally challenging as allosteric sites are frequently not apparent within X-ray structures and their role in kinase function is not always obvious. As such, there is currently a general lack of assays capable of rapidly identifying allosteric kinase inhibitors. In this report, we describe an assay for detecting allosteric ligand binding in the Abelson protein kinase domain using gas-phase protein unfolding and dissociation. Our data strongly differentiate ATP-competitive and myristate pocket-binding ligands through analyses of both gas-phase unfolding patterns and dissociative charge stripping observed in kinase-inhibitor complex ions produced by electrospray ionization. Furthermore, we discuss and quantify these results, as well as project the utility of this technique for future efforts in high-throughput kinase inhibitor discovery. (C) 2018 Elsevier B.V. All rights reserved.
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