UC Riverside

This thesis presents a comprehensive study on the crystallography of a novel SMAC mimetic, (R)-1-((S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino) propanamido) acetyl) pyrrolidine-2-carboxamido) -2,3-dihydro-1H-inden-4-yl sulfurofluoridate, also known as 142D6, and its covalent adduct formation with XIAP BIR3. The inhibitor, 142D6, was designed to simulate the binding properties of Second Mitochondria-derived Activator of Caspases (SMAC) protein, a critical regulator of apoptosis. By utilizing crystallographic techniques, we aimed to elucidate the structural basis of the interaction between 142D6 and XIAP BIR3. First, a detailed characterization of the crystal structure of 142D6 was performed, revealing its precise and tightly fitted arrangement within the domain subpockets. This structural analysis provided valuable insights into the molecular features of 142D6 that contribute to its binding specificity and potential as an inhibitor. Furthermore, the covalent adduct formation between 142D6 and XIAP BIR3 determined the complex structure, capturing the precise binding interactions between 142D6 and XIAP BIR3. This analysis highlighted a novel finding, the formation of a covalent bond between 142D6 and XIAP BIR3 Lys299 residue, shedding light on the mechanism of inhibition and the potential for irreversible inhibition strategies. By understanding the structural details of this interaction, we can gain valuable insights into the design of more potent and selective SMAC mimetics for potential clinical applications. Overall, this thesis provides a comprehensive crystallographic analysis of the novel SMAC mimetic, 142D6, and its covalent adduct formation with XIAP BIR3 at Lys299 residue. The findings presented here enhance our understanding of the structural basis of inhibition and pave the way for the development of improved apoptotic modulators with potential therapeutic application.