title: Probing the molecular and structural elements of ligands binding to the active site versus an allosteric pocket of the human farnesyl pyrophosphate synthase.
abstract: 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 sub-pockets of the active site cavity, as well as the allosteric pocket of hFPPS in the presence of the enzyme's Mg(2+) ion cofactor. These results are consistent with the previously proposed hypothesis that the allosteric pocket of hFPPS, located near the active site, plays a feed-back regulatory role for this enzyme.
authors: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
authors: Dimitrios
authors: D
authors: Gritzalis
authors: Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
authors: Jaeok
authors: J
authors: Park
authors: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
authors: Wei
authors: W
authors: Chiu
authors: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
authors: Hyungjun
authors: H
authors: Cho
authors: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
authors: Yih-Shyan
authors: YS
authors: Lin
authors: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
authors: Joris W
authors: JW
authors: De Schutter
authors: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada.
authors: Cyrus M
authors: CM
authors: Lacbay
authors: Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.
authors: Michal
authors: M
authors: Zielinski
authors: Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada; Department of Microbiology and Immunology, McGill University, 3775 Rue University, Montreal, QC H3A 2B4, Canada; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, 3649 Promenade Sir William Osler, Montréal, QC H3G 0B1, Canada.
authors: Albert M
authors: AM
authors: Berghuis
authors: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada; Groupe de Recherche Axé sur la Structure des Protéines, McGill University, 3649 Promenade Sir William Osler, Montréal, QC H3G 0B1, Canada. Electronic address: youla.tsantrizos@mcgill.ca.
authors: Youla S
authors: YS
authors: Tsantrizos
mesh_terms: D000495:Allosteric Site; D020134:Catalytic Domain; D004164:Diphosphonates / Q000737:chemistry / Q000378:metabolism*; D051228:Geranyltranstransferase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008274:Magnesium / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding
chemical_list: D004164:Diphosphonates; D008024:Ligands; D051228:Geranyltranstransferase; D008274:Magnesium
keywords: Allosteric inhibitors; Bisphosphonates; Human FPPS