5DGN

Crystal structure of human FPPS in complex with compound 13

5DGN の概要

• エントリーDOI: 10.2210/pdb5dgn/pdb
• 関連するPDBエントリー: 5DGM
• 分子名称: Farnesyl pyrophosphate synthase, 8-(naphthalen-1-yl)quinoline-2-carboxylic acid (3 entities in total)
• 機能のキーワード: transferase, isoprene biosynthesis; cholesterol biosynthesis
• 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: 40483.18

構造登録者

Rondeau, J.M.,Bourgier, E.,Lehmann, S. (登録日: 2015-08-28, 公開日: 2015-09-30, 最終更新日: 2024-05-08)

主引用文献

Marzinzik, A.L.,Amstutz, R.,Bold, G.,Bourgier, E.,Cotesta, S.,Glickman, J.F.,Gotte, M.,Henry, C.,Lehmann, S.,Hartwieg, J.C.,Ofner, S.,Pelle, X.,Roddy, T.P.,Rondeau, J.M.,Stauffer, F.,Stout, S.J.,Widmer, A.,Zimmermann, J.,Zoller, T.,Jahnke, W.
Discovery of Novel Allosteric Non-Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding.
Chemmedchem, 10:1884-1891, 2015

PubMed Abstract: Farnesyl pyrophosphate synthase (FPPS) is an established target for the treatment of bone diseases, but also shows promise as an anticancer and anti-infective drug target. Currently available anti-FPPS drugs are active-site-directed bisphosphonate inhibitors, the peculiar pharmacological profile of which is inadequate for therapeutic indications beyond bone diseases. The recent discovery of an allosteric binding site has paved the way toward the development of novel non-bisphosphonate FPPS inhibitors with broader therapeutic potential, notably as immunomodulators in oncology. Herein we report the discovery, by an integrated lead finding approach, of two new chemical classes of allosteric FPPS inhibitors that belong to the salicylic acid and quinoline chemotypes. We present their synthesis, biochemical and cellular activities, structure-activity relationships, and provide X-ray structures of several representative FPPS complexes. These novel allosteric FPPS inhibitors are devoid of any affinity for bone mineral and could serve as leads to evaluate their potential in none-bone diseases.

PubMed: 26381451
DOI: 10.1002/cmdc.201500338

実験手法

X-RAY DIFFRACTION (2.08 Å)