5DGS

Crystal structure of human FPPS in complex with the monophosphonate compound 15

5DGS の概要

• エントリーDOI: 10.2210/pdb5dgs/pdb
• 関連するPDBエントリー: 5DGM 5DGN
• 分子名称: Farnesyl pyrophosphate synthase, {(E)-2-[6-(acetylamino)-8-(naphthalen-1-yl)quinolin-2-yl]ethenyl}phosphonic 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: 40602.24

構造登録者

Rondeau, J.M.,Bourgier, E.,Lehmann, S. (登録日: 2015-08-28, 公開日: 2016-07-13, 最終更新日: 2024-05-08)

主引用文献

Jahnke, W.,Bold, G.,Marzinzik, A.L.,Ofner, S.,Pelle, X.,Cotesta, S.,Bourgier, E.,Lehmann, S.,Henry, C.,Hemmig, R.,Stauffer, F.,Hartwieg, J.C.,Green, J.R.,Rondeau, J.M.
A General Strategy for Targeting Drugs to Bone.
Angew.Chem.Int.Ed.Engl., 54:14575-14579, 2015

PubMed Abstract: Targeting drugs to their desired site of action can increase their safety and efficacy. Bisphosphonates are prototypical examples of drugs targeted to bone. However, bisphosphonate bone affinity is often considered too strong and cannot be significantly modulated without losing activity on the enzymatic target, farnesyl pyrophosphate synthase (FPPS). Furthermore, bisphosphonate bone affinity comes at the expense of very low and variable oral bioavailability. FPPS inhibitors were developed with a monophosphonate as a bone-affinity tag that confers moderate affinity to bone, which can furthermore be tuned to the desired level, and the relationship between structure and bone affinity was evaluated by using an NMR-based bone-binding assay. The concept of targeting drugs to bone with moderate affinity, while retaining oral bioavailability, has broad application to a variety of other bone-targeted drugs.

PubMed: 26457482
DOI: 10.1002/anie.201507064

実験手法

X-RAY DIFFRACTION (2.62 Å)