6C57

Crystal structure of mutant human geranylgeranyl pyrophosphate synthase (Y246D) in complex with bisphosphonate inhibitor FV0109

6C57 の概要

• エントリーDOI: 10.2210/pdb6c57/pdb
• 分子名称: Geranylgeranyl pyrophosphate synthase, {[(2-{3-[(4-fluorobenzene-1-carbonyl)amino]phenyl}thieno[2,3-d]pyrimidin-4-yl)amino]methylene}bis(phosphonic acid) (3 entities in total)
• 機能のキーワード: isoprenoid pathway, isopentenyl transferase, transferase inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75391.36

構造登録者

Park, J.,Bin, X.,Vincent, F.,Tsantrizos, Y.S.,Berghuis, A.M. (登録日: 2018-01-15, 公開日: 2018-09-05, 最終更新日: 2024-10-23)

主引用文献

Lacbay, C.M.,Waller, D.D.,Park, J.,Gomez Palou, M.,Vincent, F.,Huang, X.F.,Ta, V.,Berghuis, A.M.,Sebag, M.,Tsantrizos, Y.S.
Unraveling the Prenylation-Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors.
J. Med. Chem., 61:6904-6917, 2018

PubMed Abstract: Post-translational prenylation of the small GTP-binding proteins (GTPases) is vital to a plethora of biological processes, including cellular proliferation. We have identified a new class of thienopyrimidine-based bisphosphonate (ThP-BP) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) that block protein prenylation in multiple myeloma (MM) cells leading to cellular apoptosis. These inhibitors are also effective in blocking the proliferation of other types of cancer cells. We confirmed intracellular target engagement, demonstrated the mechanism of action leading to apoptosis, and determined a direct correlation between apoptosis and intracellular inhibition of hGGPPS. Administration of a ThP-BP inhibitor to a MM mouse model confirmed in vivo downregulation of Rap1A geranylgeranylation and reduction of monoclonal immunoglobulins (M-protein, a biomarker of disease burden) in the serum. These results provide the first proof-of-principle that hGGPPS is a valuable therapeutic target in oncology and more specifically for the treatment of multiple myeloma.

PubMed: 30016091
DOI: 10.1021/acs.jmedchem.8b00886

実験手法

X-RAY DIFFRACTION (3.5 Å)