Probing the molecular and structural elements of ligands binding to the active site versus an allosteric pocket of the human farnesyl pyrophosphate synthase

被引：14
作者：
Gritzalis, Dimitrios [1 ,2 ]
Park, Jaeok
Chiu, Wei [1 ]
Cho, Hyungjun [1 ]
Lin, Yih-Shyan [1 ]
De Schutter, Joris W. [1 ]
Lacbay, Cyrus M. [1 ]
Zielinski, Michal [2 ]
Berghuis, Albert M. [2 ,3 ,4 ]
Tsantrizos, Youla S. [1 ,2 ,4 ]
机构：
[1] McGill Univ, Dept Chem, Montreal, PQ H3A 0B8, Canada
[2] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada
[3] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada
[4] McGill Univ, Grp Rech Axe Struct Prot, Montreal, PQ H3G 0B1, Canada
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 05期
基金：
加拿大自然科学与工程研究理事会;
关键词：
Bisphosphonates; Human FPPS; Allosteric inhibitors; NITROGEN-CONTAINING BISPHOSPHONATES; BIOLOGICAL EVALUATION; PROTONATION; INHIBITORS; ANALOGS; DESIGN; POTENT;
D O I：
10.1016/j.bmcl.2014.12.089
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
In order to explore the interactions of bisphosphonate ligands with the active site and an allosteric pocket of the human farnesyl pyrophosphate synthase (hFPPS), substituted indole and azabenzimidazole bisphosphonates were designed as chameleon ligands. NMR and crystallographic studies revealed that these compounds can occupy both subpockets of the active site cavity, as well as the allosteric pocket of hFPPS in the presence of the enzyme's Mg2+ ion cofactor. These results are consistent with the previously proposed hypothesis that the allosteric pocket of hFPPS, located near the active site, plays a feedback regulatory role for this enzyme. (C) 2015 Elsevier Ltd. All rights reserved.
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收藏
页码：1117 / 1123
页数：7
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