Engineering a Functional Dimeric Mutant Form of GGPPS to Produce High-resolution Crystal Structures of Inhibitor-enzyme Complexes

Monday, Jan. 16, 1-2 p.m.

CSF-1302

Sean Ezekiel

Ph.D Student

Department of Biochemistry

January 16, 2023

1:00pm – 2:00pm.

CSF 1302

The direct link for the meeting is:

https://mun.webex.com/mun/j.php?MTID=mf788170b109365e030a78be82b7ac0df

Abstract:

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.

Presented by Department of Biochemistry

Event Listing 2023-01-16 13:00:00 2023-01-16 14:00:00 America/St_Johns Engineering a Functional Dimeric Mutant Form of GGPPS to Produce High-resolution Crystal Structures of Inhibitor-enzyme Complexes Sean Ezekiel Ph.D Student Department of Biochemistry January 16, 2023 1:00pm – 2:00pm. CSF 1302 The direct link for the meeting is: https://mun.webex.com/mun/j.php?MTID=mf788170b109365e030a78be82b7ac0df Abstract: 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. CSF-1302 Department of Biochemistry