Phillips, George NTao, Yhizi J2023-08-092023-08-092023-082023-04-26August 202Kosgei, 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>.https://hdl.handle.net/1911/115212The 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.application/pdfengCopyright 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.EnediyneLysyl HydroxylaseCalicheamicinMolecular ReplacementMicromonospora echinosporaMicromonospora chersinaDynemicinBiosynthetic Gene ClusterThesis2023-08-09