4JVJ

Crystal structure of human FPPS in complex with magnesium, CL01131, and sulfate

4JVJ の概要

• エントリーDOI: 10.2210/pdb4jvj/pdb
• 関連するPDBエントリー: 4L2X
• 分子名称: Farnesyl pyrophosphate synthase, ({[6-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}methanediyl)bis(phosphonic acid), SULFATE ION, ... (5 entities in total)
• 機能のキーワード: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P14324
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43729.26

構造登録者

Park, J.,Leung, C.-Y.,Tsantrizos, Y.S.,Berghuis, A.M. (登録日: 2013-03-25, 公開日: 2014-01-01, 最終更新日: 2023-09-20)

主引用文献

Leung, C.Y.,Park, J.,De Schutter, J.W.,Sebag, M.,Berghuis, A.M.,Tsantrizos, Y.S.
Thienopyrimidine Bisphosphonate (ThPBP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Optimization and Characterization of the Mode of Inhibition.
J.Med.Chem., 56:7939-7950, 2013

PubMed Abstract: Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug risedronic acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.

PubMed: 23998921
DOI: 10.1021/jm400946f

実験手法

X-RAY DIFFRACTION (2.8 Å)