Structural Interrogation of Potential Drug-Discovery Proteins Using X-ray Crystallography and Electron Microscopy

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dc.contributor.advisorPhillips, George Nen_US
dc.contributor.advisorTao, Yhizi Jen_US
dc.creatorKosgei, Abigael Jesangen_US
dc.date.accessioned2023-08-09T19:46:42Zen_US
dc.date.available2023-08-09T19:46:42Zen_US
dc.date.created2023-08en_US
dc.date.issued2023-04-26en_US
dc.date.submittedAugust 2023en_US
dc.date.updated2023-08-09T19:46:42Zen_US
dc.description.abstractThe enediynes natural products have shown great potential as anticancer antibiotics. They bind to the minor groove of DNA in such a way that they can abstract hydrogen atoms from the sugars of the opposite strands causing double stranded or single stranded DNA scission. The availability of the biosynthetic gene cluster of enediynes have paved the way to the in vitro studies of the genes and their involvement in the synthesis of these unique molecules. Structural studies of two proteins CalU17 and DynF, encoded by genes involved in the biosynthesis of 10-membered ring enediynes, calicheamicin (CAL) and dynemicin (DYN) respectively using X-ray crystallography is reported here. The goal was to understand the role each protein plays in their respective biosynthetic pathways. This data will further expand our abilities to modify and generate a library of novel small molecules that will be used for drug screening in the future. Lysyl hydroxylase 2 (LH2) hydroxylates telopeptidyl lysine in collagen. The hydroxylated collagen is further processed to form hydroxylysine aldehyde-derived collagen cross-links (HLCCs) predominant in skeletal tissues. HLCCs alter stromal stiffness and influence the metastatic fate of tumor cells by promoting fibrosis and cancer progression. Structural determination of full-length human LH2 protein will enable us to gain insights on the mechanism of action of the enzyme to substrate (collagen) binding. This may help develop an antagonist targeting LH2 for cancer treatment.en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationKosgei, Abigael Jesang. "Structural Interrogation of Potential Drug-Discovery Proteins Using X-ray Crystallography and Electron Microscopy." (2023) Diss., Rice University. <a href="https://hdl.handle.net/1911/115212">https://hdl.handle.net/1911/115212</a>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/115212en_US
dc.language.isoengen_US
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.subjectEnediyneen_US
dc.subjectLysyl Hydroxylaseen_US
dc.subjectCalicheamicinen_US
dc.subjectMolecular Replacementen_US
dc.subjectMicromonospora echinosporaen_US
dc.subjectMicromonospora chersinaen_US
dc.subjectDynemicinen_US
dc.subjectBiosynthetic Gene Clusteren_US
dc.titleStructural Interrogation of Potential Drug-Discovery Proteins Using X-ray Crystallography and Electron Microscopyen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBiochemistry and Cell Biologyen_US
thesis.degree.disciplineNatural Sciencesen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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