9HJS

Crystal structure of human geranylgeranyl diphosphate synthase mutant R235C

9HJS の概要

• エントリーDOI: 10.2210/pdb9hjs/pdb
• 分子名称: Geranylgeranyl pyrophosphate synthase, GERANYLGERANYL DIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: multiple myeloma, ggpps-r235c, geranylgeranyl diphosphate, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 215287.70

構造登録者

Yehia, R.,Giladi, M.,Haitin, Y. (登録日: 2024-12-01, 公開日: 2025-06-25, 最終更新日: 2025-12-10)

主引用文献

Yehia, R.,Portasikova, J.M.,Mor Yosef, R.,Da'adoosh, B.,Kadek, A.,Man, P.,Giladi, M.,Haitin, Y.
A somatic multiple myeloma mutation unravels a mechanism of oligomerization-mediated product inhibition in GGPPS.
Febs J., 292:5802-5817, 2025

PubMed Abstract: Protein prenylation plays a critical role in regulating the cellular localization of small GTPases and is essential for multiple myeloma (MM) pathology. Geranylgeranyl diphosphate synthase (GGPPS), producing a key prenylation moiety, exists in a dimeric or hexameric form, depending on the species. However, the functional significance of this oligomerization remains unclear. Using crystallography, mass spectrometry, and fluorescence spectroscopy, we show that the GGPPS mutant-found in the widely studied MM cell line RPMI-8226-exhibits weakened inter-dimer interactions, reduced hexamer stability, and increased apparent substrate affinity and product release kinetics. These effects are even more pronounced in a dimeric mutant, GGPPS, demonstrating that interdimer interactions within the hexamer help stabilize a lid region over the active site, thereby stabilizing product binding in an inhibitory conformation. Together, these findings reveal that hexamerization regulates GGPPS activity through product inhibition and underscore the importance of cell line selection and characterization in drug discovery efforts.

PubMed: 40621901
DOI: 10.1111/febs.70181

実験手法

X-RAY DIFFRACTION (2.51 Å)