Engineering a functional dimeric mutant form of GGPPS to produce high-resolution crystal structures of inhibitor-enzyme complexes

Sean Ezekiel 
PhD Student
Department of Biochemistry


Date: January 16, 2023
Time: 1:00 p.m. to 2:00 p.m. 
Room: CSF 1302

The enzyme human geranylgeranyl pyrophosphate synthase (GGPPS) catalyzes the production of geranylgeranyl pyrophosphate (GGPP), an isoprenoid that plays a key role in cell signalling. Owing to its implications in cellular processes involved in multiple forms of cancer as well as Alzheimer’s disease, GGPPS has been studied extensively. However, efforts to elucidate its detailed structure through X-ray crystallography have been mostly unsuccessful. The difficulty is attributed to GGPPS’s oligomeric structure (a hexameric complex consisting of three dimers). Interestingly, the dimeric enzyme human farnesyl pyrophosphate synthase shares a similar monomeric structure with GGPPS yet is more readily crystallized. Given the similarity between the monomers of both enzymes, we hypothesized that a dimeric mutant form of GGPPS would produce a high-resolution crystal structure. To this end, our lab has successfully engineered three separate mutant dimers of GGPPS. I am currently characterizing the mutant dimers and assessing their potential as effective study tools in structure-based drug design.