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dc.contributor.advisorMaly, Dustin J
dc.contributor.authorRegister, Ames C.
dc.date.accessioned2017-02-14T22:37:24Z
dc.date.submitted2016-08
dc.identifier.otherRegister_washington_0250E_16510.pdf
dc.identifier.urihttp://hdl.handle.net/1773/38087
dc.descriptionThesis (Ph.D.)--University of Washington, 2016-08
dc.description.abstractProtein kinases are a large family of enzymes that play integral roles in cell signaling networks and are thus critical for effecting appropriate cellular responses to environmental stimuli. Much of kinase biological function has been studied in terms of catalytic activity: phosphorylation of substrate proteins as part of signaling cascades. However, recent evidence has shown that kinases play many important non-catalytic functions such as DNA-binding, scaffolding, and participating in a variety of physiologically relevant protein-protein interactions. While critical, these roles have not been thoroughly explored, in large part due to limited availability of selective ATP-competitive inhibitors. Selectivity for a specific kinase is difficult to achieve due to high structural homology between the ATP-binding sites of the 518 human kinases. Additionally, it has been shown over the past two decades that it is possible to stabilize structurally distinct ATP-binding site conformations using conformation-selective inhibitors, termed Type I and Type II inhibitors, in many kinases. In several cases, inhibition of kinase ATP-binding sites with Type I or Type II inhibitors has been shown to divergently affect cell signaling events as a result of allosteric coupling between important structural features in the ATP-binding site and distal protein-protein interaction sites on the inhibited kinase. Thus, it is important not only to build selective ATP-competitive inhibitors but to understand how their binding affects global kinase conformation through allosteric coupling. This thesis describes my work characterizing allosteric networks in multi-domain tyrosine kinases (Src-Family Kinases (SFKs) and Abl) using conformation-selective inhibitors as well as developing a method for using conformation-selective inhibitors in cells to better understand how non-catalytic function of a kinase of interest determines its role in cell signaling networks.
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.rights
dc.subjectAbleson tyrosine kinase
dc.subjectAllosteric regulation
dc.subjectcell signaling
dc.subjectConformation-selective inhibition
dc.subjectSmall molecule inhibition
dc.subjectSrc-family kinase
dc.subject.otherChemistry
dc.subject.otherBiochemistry
dc.subject.otherOrganic chemistry
dc.subject.otherchemistry
dc.titleCharacterization and Exploitation of Bidirectional Allosteric Coupling in Multi-Domain Tyrosine Kinases using Conformation-Selective ATP-Competitive Inhibitors
dc.typeThesis
dc.embargo.termsRestrict to UW for 1 year -- then make Open Access
dc.embargo.lift2018-02-14T22:37:24Z


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