5JV1

Crystal structure of human FPPS in complex with an allosteric inhibitor CL-08-066

5JV1 の概要

• エントリーDOI: 10.2210/pdb5jv1/pdb
• 関連するPDBエントリー: 5JUZ 5JV0 5JV2
• 分子名称: Farnesyl pyrophosphate synthase, SULFATE ION, [(1R)-1-{[6-(3-chloro-4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}-2-(3-fluorophenyl)ethyl]phosphonic acid, ... (4 entities in total)
• 機能のキーワード: transferase, 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: 44292.86

構造登録者

Park, J.,Leung, C.Y.,Tsantrizos, Y.S.,Berghuis, A.M. (登録日: 2016-05-10, 公開日: 2017-03-15, 最終更新日: 2023-09-27)

主引用文献

Park, J.,Leung, C.Y.,Matralis, A.N.,Lacbay, C.M.,Tsakos, M.,Fernandez De Troconiz, G.,Berghuis, A.M.,Tsantrizos, Y.S.
Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase.
J. Med. Chem., 60:2119-2134, 2017

PubMed Abstract: The human farnesyl pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into nonskeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating nonskeletal diseases. Hit-to-lead optimization of a new series of thienopyrimidine-based monosphosphonates (ThP-MPs) led to the identification of analogs with nanomolar potency in inhibiting hFPPS. Their interactions with the allosteric pocket of the enzyme were characterized by crystallography, and the results provide further insight into the pharmacophore requirements for allosteric inhibition.

PubMed: 28208018
DOI: 10.1021/acs.jmedchem.6b01888

実験手法

X-RAY DIFFRACTION (2.3 Å)