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dc.contributor.authorFaoro, Camilla
dc.date.accessioned2019-03-18
dc.date.issued2018-11-08
dc.identifier.urihttp://hdl.handle.net/2123/20168
dc.descriptionIncludes publicationsen_AU
dc.description.abstractThe Signal Recognition Particle (SRP) is an essential ribonucleoprotein complex responsible for co-translational delivery of membrane and secretory proteins to the plasma membrane in prokaryotes and to the endoplasmic reticulum in eukaryotes. In Eubacteria, SRP consists of the GTPase Ffh and the small 4.5S RNA; in eukaryotes, the system is more complex and SRP comprises six proteins (the heterodimer SRP 9/14, SRP 19, SRP 54, and the heterodimer SRP 68/72) along with a large RNA moiety, the 7SL RNA. SRP has been reported to be involved in many cellular processes outside the SRP-targeting cycle. Two layers of the SRP interactome, the SRP proteome and SRP transcriptome, were analysed by LC-MS/MS and RIP-seq, respectively. The majority of identified RNA and protein targets of the SRP subunits have nucleic-acid, chromatin and protein-binding functions and are involved in ribonucleoprotein particles (RNPs) formation, RNA processing and protein transport. Confocal microscopy studies showed that SRP subunits localizes in a dynamic manner during the cell cycle, indicating a spatial-temporal regulation of SRP-binding partners. Truncations or mutations on any of the bacterial components of the SRP system have proven to be either lethal or severely impact cell viability. Here, we propose the bacterial SRP and its interactions with the cognate SRP receptor, FtsY, as an ideal target for the development of novel antibiotics. Using a Fragment-Based Drug Design approach we have identified three fragments from a commercial library that bind to FtsY. We have crystallized FtsY in an Apo form and soaked GTP analogues as well as the three fragments and analogues and determined their X-ray crystal structures at resolution ranging from 1.221.9 Å. Despite the low affinity of the compounds, we were able to identify unambiguously their binding site and show that soaking of fragments, even at low affinity, is possible to aid in our drug discovery project.en_AU
dc.rightsThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
dc.subjectSRPen_AU
dc.subjectprotein targetingen_AU
dc.subjectribonucleoprotein complexen_AU
dc.subjectSRPomeen_AU
dc.titleThe Signal Recognition Particle: noncanonical functions and drug discoveryen_AU
dc.typeThesisen_AU
dc.description.embargo2020-03-18
dc.type.thesisDoctor of Philosophyen_AU
usyd.facultyFaculty of Science, School of Life and Environmental Sciencesen_AU
usyd.degreeDoctor of Philosophy Ph.D.en_AU
usyd.awardinginstThe University of Sydneyen_AU


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