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dc.contributor.advisorMankin, Alexanderen_US
dc.contributor.authorSothiselvam, Shanmugapriyaen_US
dc.date.accessioned2016-07-01T20:50:21Z
dc.date.available2016-07-01T20:50:21Z
dc.date.created2016-05en_US
dc.date.issued2016-07-01
dc.date.submitted2016-05en_US
dc.identifier.urihttp://hdl.handle.net/10027/20805
dc.description.abstractTranslation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. We show that ‘R/K-X-R/K’ is one such problematic sequence for drug bound ribosomes to synthesize. Peptide bond formation is inhibited between positively charged donor and acceptor substrates in the drug bound ribosome. Further, we elucidate how the nature of the amino acids preceding the arrest sequence in the peptide also impacts translation arrest. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome and how a predisposed ribosome inhibits catalysis between specific donor and acceptor substrates by discriminating them based on their charge and size.en_US
dc.language.isoenen_US
dc.rightsen_US
dc.rightsCopyright 2016 Shanmugapriya Sothiselvamen_US
dc.subjectTranslationen_US
dc.subjectRibosomeen_US
dc.subjectMacrolidesen_US
dc.subjectAntibiotic Resistanceen_US
dc.subjectNascent peptideen_US
dc.titleFunctional Interactions Between Ribosome and Nascent Peptide Mediated By Small Moleculesen_US
thesis.degree.departmentMedicinal Chemistry and Pharmacognosyen_US
thesis.degree.disciplinePharmacognosyen_US
thesis.degree.grantorUniversity of Illinois at Chicagoen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhD, Doctor of Philosophyen_US
dc.type.genrethesisen_US
dc.contributor.committeeMemberFederle, Michaelen_US
dc.contributor.committeeMemberKay, Brianen_US
dc.contributor.committeeMemberSimonovic, Miljanen_US
dc.contributor.committeeMemberVazquez-Laslop, Noraen_US
dc.contributor.committeeMemberPolikanov, Yuryen_US
dc.type.materialtexten_US


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