4NFK

Crystal structure of human FPPS in complex with nickel, JDS05120, and sulfate

4NFK の概要

• エントリーDOI: 10.2210/pdb4nfk/pdb
• 関連するPDBエントリー: 4NFI 4NFJ
• 分子名称: Farnesyl pyrophosphate synthase, NICKEL (II) ION, [({5-[4-(cyclopropyloxy)phenyl]pyridin-3-yl}amino)methanediyl]bis(phosphonic acid), ... (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: 43817.38

構造登録者

Park, J.,De schutter, J.W.,Tsantrizos, Y.S.,Berghuis, A.M. (登録日: 2013-10-31, 公開日: 2014-12-31, 最終更新日: 2023-09-20)

主引用文献

Park, J.,Rodionov, D.,De Schutter, J.W.,Lin, Y.S.,Tsantrizos, Y.S.,Berghuis, A.M.
Crystallographic and thermodynamic characterization of phenylaminopyridine bisphosphonates binding to human farnesyl pyrophosphate synthase.
PLoS ONE, 12:e0186447-e0186447, 2017

PubMed Abstract: Human farnesyl pyrophosphate synthase (hFPPS) catalyzes the production of the 15-carbon isoprenoid farnesyl pyrophosphate. The enzyme is a key regulator of the mevalonate pathway and a well-established drug target. Notably, it was elucidated as the molecular target of nitrogen-containing bisphosphonates, a class of drugs that have been widely successful against bone resorption disorders. More recently, research has focused on the anticancer effects of these inhibitors. In order to achieve increased non-skeletal tissue exposure, we created phenylaminopyridine bisphosphonates (PNP-BPs) that have bulky hydrophobic side chains through a structure-based approach. Some of these compounds have proven to be more potent than the current clinical drugs in a number of antiproliferation assays using multiple myeloma cell lines. In the present work, we characterized the binding of our most potent PNP-BPs to the target enzyme, hFPPS. Co-crystal structures demonstrate that the molecular interactions designed to elicit tighter binding are indeed established. We carried out thermodynamic studies as well; the newly introduced protein-ligand interactions are clearly reflected in the enthalpy of binding measured, which is more favorable for the new PNP-BPs than for the lead compound. These studies also indicate that the affinity of the PNP-BPs to hFPPS is comparable to that of the current drug risedronate. Risedronate forms additional polar interactions via its hydroxyl functional group and thus exhibits more favorable binding enthalpy; however, the entropy of binding is more favorable for the PNP-BPs, owing to the greater desolvation effects resulting from their large hydrophobic side chains. These results therefore confirm the overall validity of our drug design strategy. With a distinctly different molecular scaffold, the PNP-BPs described in this report represent an interesting new group of future drug candidates. Further investigation should follow to characterize the tissue distribution profile and assess the potential clinical benefits of these compounds.

PubMed: 29036218
DOI: 10.1371/journal.pone.0186447

実験手法

X-RAY DIFFRACTION (1.85 Å)