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Plasmodium vivax geranylgeranylpyrophosphate synthase in complex with IPP and zoledronate
PDB Code 3EZ3 Protein Family Transferases Target PP-GGPPS Alias n/a Disease Area/Function parasitic disease Date Deposited 2008-10-22 Authors
About this structure
Humans and other animals produce IPP and DMAPP via the mevalonic acid (MVA) pathway, which are used to make longer-chained pyrophosphates by enzymes such as farnesyl pyrophosphate synthase (FPPS) and geranylgeranylpyrophosphate synthase. Both of these human enzymes have been characterized and found to profuce strictly one product - respectively FPP and GGPP. The proteins encoded by the gene PF11_0295 and Pv092040 respectively in the Plasmodium falciparum and Plasmodium vivax genomes are sequentially homologous to both human FPPS and GGPPS, but slightly closer to FPPS. Our crystallographic structure of Pv092040 also shows a fold that more closely resembles hFPPS. Interestingly, our experiments show that these proteins from malaria parasites produce GGPPS in biochemical assays. Furthermore, this Plasmodium enzyme can be inhibited by nitrogen-containing bisphosphonates at mid-nanomolar concentrations, which is common of FPPS but not GGPPS from other orgnanisms.We have previously solved the apo structure of Pv-GGPPS (2IHI). This new structure features zoledronate and magnesium bound in roughly the same positions as they are found in the human FPPS structure (1ZW5). Just as in many structures of FPPS, there are three magnesium ions bound (as shown in green in the figure), whereas all previous GGPPS structures have at most 2 magnesium ions. We propose that this distinction may at least in part explain the inhibition of PvGGPPS by N-BPs.
