3N49

Human FPPS COMPLEX WITH NOV_292

3N49 の概要

• エントリーDOI: 10.2210/pdb3n49/pdb
• 関連するPDBエントリー: 3N1V 3N1W 3N3L 3N45 3N46 3N5H 3N5J 3N6K
• 分子名称: FARNESYL PYROPHOSPHATE SYNTHASE, naphtho[2,1-b]thiophen-1-ylacetic acid, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: bisphosphonate; fragment-based screening; transferase; isoprene biosynthesis; cholesterol biosynthesis, ransferase-transferase inhibitor complex, 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: 40521.12

構造登録者

Rondeau, J.-M. (登録日: 2010-05-21, 公開日: 2010-08-18, 最終更新日: 2024-02-21)

主引用文献

Jahnke, W.,Rondeau, J.M.,Cotesta, S.,Marzinzik, A.,Pelle, X.,Geiser, M.,Strauss, A.,Gotte, M.,Bitsch, F.,Hemmig, R.,Henry, C.,Lehmann, S.,Glickman, J.F.,Roddy, T.P.,Stout, S.J.,Green, J.R.
Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery.
Nat.Chem.Biol., 6:660-666, 2010

PubMed Abstract: Bisphosphonates are potent inhibitors of farnesyl pyrophosphate synthase (FPPS) and are highly efficacious in the treatment of bone diseases such as osteoporosis, Paget's disease and tumor-induced osteolysis. In addition, the potential for direct antitumor effects has been postulated on the basis of in vitro and in vivo studies and has recently been demonstrated clinically in early breast cancer patients treated with the potent bisphosphonate zoledronic acid. However, the high affinity of bisphosphonates for bone mineral seems suboptimal for the direct treatment of soft-tissue tumors. Here we report the discovery of the first potent non-bisphosphonate FPPS inhibitors. These new inhibitors bind to a previously unknown allosteric site on FPPS, which was identified by fragment-based approaches using NMR and X-ray crystallography. This allosteric and druggable pocket allows the development of a new generation of FPPS inhibitors that are optimized for direct antitumor effects in soft tissue.

PubMed: 20711197
DOI: 10.1038/nchembio.421

実験手法

X-RAY DIFFRACTION (2.5 Å)