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dc.contributor.advisorHwang, Tzyh-Changeng
dc.contributor.authorTsai, Ming-Feng, 1985eng
dc.date.issued2010eng
dc.date.submitted2010 Falleng
dc.description.abstractThe cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride ion channel whose defects cause the deadly genetic disease cystic fibrosis (CF). Like other ATP binding cassette (ABC) proteins, CFTR encompasses two cytoplasmic nucleotide binding domains (NBDs). Upon ATP binding, the two NBDs can coalesce into a head-to-tail dimer with ATP buried at two interfacial composite sites (sites 1 and 2). Although evidence suggests that gating of CFTR is mainly controlled by site 2, the role of site 1 remains less understood. I have used pyrophosphate as a probe or adopted a ligand exchange protocol to investigate ATP binding status in site 1 in real time. With these novel approaches, I have identified a “partial” NBD dimer state mediated by an ATP molecule tightly bound in site 1. A molecular model of CFTR gating was then established with opening and closing of CFTR coupled to the formation and partial separation of the NBD dimer. Moreover, I discovered several mutations that enhance ATP binding in site 1 and demonstrated that the activity of CF-associated mutant channels, ΔF508- and G551D-CFTR, can be significantly improved by these mutations, thus providing evidence that site 1 is a potential target for developing pharmaceutical reagents to treat patients with CF.eng
dc.format.extentix, 194 pageseng
dc.identifier.urihttp://hdl.handle.net/10355/41916
dc.languageEnglisheng
dc.publisherUniversity of Missouri--Columbiaeng
dc.relation.ispartofcommunityUniversity of Missouri--Columbia. Graduate School. Theses and Dissertationseng
dc.rightsOpenAccess.eng
dc.rights.licenseThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.
dc.subjectCystic fibrosiseng
dc.subjectPatch clampeng
dc.subjectABC transportereng
dc.subjectElectrophysiologyeng
dc.subjectDrug designeng
dc.subject.FASTCystic fibrosis - Researcheng
dc.subject.FASTPyrophosphateseng
dc.subject.FASTATP-binding cassette transporterseng
dc.subject.FASTBinding sites (Biochemistry) - Analysiseng
dc.titleFunctional and pharmacological importance of the composite ATP binding site 1 in CFTR chloride channelseng
dc.typeThesiseng
thesis.degree.disciplinePhysiology (Medicine) (MU)eng
thesis.degree.grantorUniversity of Missouri--Columbiaeng
thesis.degree.levelDoctoraleng
thesis.degree.namePh. D.eng


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