Grant: Undergraduate Student Research Awards (USRA)

"Geranylgeranyl pyrophosphate synthase (GGPPS) catalyzes the production of geranylgeranyl pyrophosphate (GGPP), a key isoprenoid required for protein prenylation. Geranylgeranylation of small GTPases, such as Rho proteins, is essential for their membrane localization and proper function in signal transduction. Despite its biological importance and potential as a therapeutic target, structural characterization of GGPPS and its interactions with small molecules has been limited by its poor crystallization propensity. To address this challenge, we have engineered mutant variants of GGPPS that serve as tractable models for structural and mechanistic studies. One such variant recently yielded a high-resolution (<2 Å) X-ray crystal structure, revealing GGPP bound in a product-mediated feedback inhibitory mode. Building on this foundation, we now aim to characterize the binding of GGPPS substrates, as well as known bisphosphonate inhibitors. These studies will provide mechanistic insights into substrate recognition, catalysis, and inhibition, while further validating the utility of the engineered variants as tools for structural enzymology. In parallel, this project will support inclusive training in biochemical research by providing hands-on experience and skill development opportunities for students from diverse backgrounds."