Metal coordination is crucial for geranylgeranyl diphosphate synthase–bisphosphonate interactions: A crystallographic and computational analysis

Michal Lisnyansky, Elon Yariv, Omri Segal, Milit Marom, Anat Loewenstein, Nir Ben-Tal, Moshe Giladi*, Yoni Haitin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Geranylgeranyl diphosphate synthase (GGPPS) is a central metalloenzyme in the mevalonate pathway, crucial for the prenylation of small GTPases. As small GTPases are pivotal for cellular survival, GGPPS was highlighted as a potential target for treating human diseases, including solid and hematologic malignancies and parasitic infections. Most available GGPPS inhibitors are bisphosphonates, but the clinically available compounds demonstrate poor pharmacokinetic properties. Although the design of novel bisphosphonates with improved physicochemical properties is highly desirable, the structure of wild-type human GGPPS (hGGPPS) bound to a bisphosphonate has not been resolved. Moreover, various metal-bisphosphonate–binding stoichiometries were previously reported in structures of yeast GGPPS (yGGPPS), hampering computational drug design with metal-binding pharmacophores (MBP). In this study, we report the 2.2 Å crystal structure of hGGPPS in complex with ibandronate, clearly depicting the involvement of three Mg2+ ions in bisphosphonate–protein interactions. Using drug-binding assays and computational docking, we show that the assignment of three Mg2+ ions to the binding site of both hGGPPS and yGGPPS greatly improves the correlation between calculated binding energies and experimentally measured affinities. This work provides a structural basis for future rational design of additional MBP-harboring drugs targeting hGGPPS. SIGNIFICANCE STATEMENT Bisphosphonates are inhibitors of geranylgeranyl diphosphate synthase (GGPPS), a metalloenzyme crucial for cell survival. Bisphosphonate binding depends on coordination by Mg2+ ions, but various Mg2+-bisphosphonate–binding stoichiometries were previously reported. In this study, we show that three Mg2+ ions are vital for drug binding and provide a structural basis for future computational design of GGPPS inhibitors.

Original languageEnglish
Pages (from-to)580-588
Number of pages9
JournalMolecular Pharmacology
Volume96
Issue number5
DOIs
StatePublished - Nov 2019

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