Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
Mol Cancer Ther. 2024 Jan 3;23(1):14-23. doi: 10.1158/1535-7163.MCT-23-0358.
Geranylgeranyl diphosphate synthase (GGDPS), the source of the isoprenoid donor in protein geranylgeranylation reactions, has become an attractive target for anticancer therapy due to the reliance of cancers on geranylgeranylated proteins. Current GGDPS inhibitor development focuses on optimizing the drug-target enzyme interactions of nitrogen-containing bisphosphonate-based drugs. To advance GGDPS inhibitor development, understanding the enzyme structure, active site, and ligand/product interactions is essential. Here we provide a comprehensive structure-focused review of GGDPS. We reviewed available yeast and human GGDPS structures and then used AlphaFold modeling to complete unsolved structural aspects of these models. We delineate the elements of higher-order structure formation, product-substrate binding, the electrostatic surface, and small-molecule inhibitor binding. With the rise of structure-based drug design, the information provided here will serve as a valuable tool for rationally optimizing inhibitor selectivity and effectiveness.
香叶基二磷酸合酶（GGDPS）是蛋白质香叶基化反应中异戊烯供体的来源，由于癌症依赖于香叶基化蛋白，因此它已成为癌症治疗的一个有吸引力的靶点。目前的 GGDPS 抑制剂开发侧重于优化含氮双膦酸盐类药物与药物靶酶的相互作用。为了推进 GGDPS 抑制剂的开发，了解酶的结构、活性位点和配体/产物相互作用至关重要。在这里，我们提供了一个全面的以结构为重点的 GGDPS 综述。我们回顾了现有的酵母和人类 GGDPS 结构，然后使用 AlphaFold 建模来完成这些模型中未解决的结构方面。我们描述了高级结构形成、产物-底物结合、静电表面和小分子抑制剂结合的要素。随着基于结构的药物设计的兴起，这里提供的信息将成为合理优化抑制剂选择性和有效性的有价值工具。
