Structural Insight into Geranylgeranyl Diphosphate Synthase (GGDPS) for Cancer Therapy

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Geranylgeranyl diphosphate synthase (GGDPS) is crucial for protein geranylgeranylation, a process vital for cancer cell survival.
• Cancers' reliance on geranylgeranylated proteins makes GGDPS an attractive target for anticancer drug development.
• Current inhibitors, primarily nitrogen-containing bisphosphonates, require optimization for improved drug-target interactions.

Approach:

• This study provides a comprehensive, structure-focused review of GGDPS.
• Available crystal structures of yeast and human GGDPS were analyzed.
• AlphaFold modeling was employed to elucidate unsolved structural aspects and complete existing models.

Key Points:

• Detailed analysis of GGDPS higher-order structure formation and active site.
• Delineation of product-substrate binding mechanisms and electrostatic surface potentials.
• Characterization of small-molecule inhibitor binding interactions within the GGDPS active site.

Conclusions:

• Understanding GGDPS structure, active site, and ligand interactions is essential for advancing inhibitor development.
• The comprehensive structural insights presented will facilitate rational optimization of inhibitor selectivity and efficacy.
• This review serves as a valuable resource for structure-based drug design targeting GGDPS in cancer therapy.