title: Protonation State and Hydration of Bisphosphonate Bound to Farnesyl Pyrophosphate Synthase.
abstract: Farnesyl pyrophosphate synthase (FPPS) catalyzes the condensation of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate to FPP and is known to be a molecular target of osteoporosis drugs, such as risedronate (RIS), which is a nitrogen-containing bisphosphonate. The protonation states and hydration structure of RIS bound to FPPS were determined by neutron protein crystallography, which allows direct visualization of hydrogens and deuteriums. The structure analysis revealed that the phosphate groups of RIS were fully deprotonated with the abnormally decreased pKa, and that the roles of E93 and D264 consisted of canceling the extra negative charges upon the binding of ligands. Collectively, our neutron structures provided insights into the physicochemical properties during the bisphosphonate binding event.
authors: Faculty of Pharmaceutical Sciences, University of Toyama , 2630 Sugitani, Toyama 930-0914, Japan.
authors: Takeshi
authors: T
authors: Yokoyama
authors: Faculty of Pharmaceutical Sciences, University of Toyama , 2630 Sugitani, Toyama 930-0914, Japan.
authors: Mineyuki
authors: M
authors: Mizuguchi
authors: Heinz Maier-Leibnitz Zentrum (MLZ), Technische Universität München , Lichtenbergstrasse 1, 85748 Garching, Germany.
authors: Andreas
authors: A
authors: Ostermann
authors: Frontier Research Center for Applied Atomic Sciences, Ibaraki University , 162-1 Shirakata, Tokai, Ibaraki 319-1106, Japan.
authors: Katsuhiro
authors: K
authors: Kusaka
authors: Frontier Research Center for Applied Atomic Sciences, Ibaraki University , 162-1 Shirakata, Tokai, Ibaraki 319-1106, Japan.
authors: Nobuo
authors: N
authors: Niimura
authors: Jülich Centre for Neutron Science (JCNS) at Heinz Maier-Leibnitz Zentrum (MLZ), Forschungszentrum Jülich GmbH, Lichtenbergstr. 1, 85747 Garching, Germany.
authors: Tabias E
authors: TE
authors: Schrader
authors: Frontier Research Center for Applied Atomic Sciences, Ibaraki University , 162-1 Shirakata, Tokai, Ibaraki 319-1106, Japan.|College of Engineering, Ibaraki University , Naka-Narusawa 4-12-1, Hitachi, Ibaraki 316-8511, Japan.
authors: Ichiro
authors: I
authors: Tanaka
mesh_terms: D050071:Bone Density Conservation Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003903:Deuterium / Q000737:chemistry; D051228:Geranyltranstransferase / Q000737:chemistry*; D045782:Hemiterpenes / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry*; D008274:Magnesium / Q000737:chemistry; D008958:Models, Molecular; D033363:Neutron Diffraction; D009943:Organophosphorus Compounds / Q000737:chemistry; D011487:Protein Conformation; D011522:Protons; D000068296:Risedronic Acid / Q000737:chemistry*
chemical_list: D050071:Bone Density Conservation Agents; D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D011522:Protons; C004809:isopentenyl pyrophosphate; D006859:Hydrogen; D003903:Deuterium; D051228:Geranyltranstransferase; D008274:Magnesium; D000068296:Risedronic Acid