Crystallization and preliminary neutron diffraction experiment of human farnesyl pyrophosphate synthase complexed with risedronate.
Nitrogen-containing bisphosphonates (N-BPs), such as risedronate and zoledronate, are currently used as a clinical drug for bone-resorption diseases and are potent inhibitors of farnesyl pyrophosphate synthase (FPPS). X-ray crystallographic analyses of FPPS with N-BPs have revealed that N-BPs bind to FPPS with three magnesium ions and several water molecules. To understand the structural characteristics of N-BPs bound to FPPS, including H atoms and hydration by water, neutron diffraction studies were initiated using BIODIFF at the Heinz Maier-Leibnitz Zentrum (MLZ). FPPS-risedronate complex crystals of approximate dimensions 2.8 × 2.5 × 1.5 mm (∼3.5 mm(3)) were obtained by repeated macro-seeding. Monochromatic neutron diffraction data were collected to 2.4 Å resolution with 98.4% overall completeness. Here, the first successful neutron data collection from FPPS in complex with N-BPs is reported.
Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0914, Japan.
Takeshi
T
Yokoyama
Heinz Maier-Leibnitz Zentrum (MLZ), Technische Universität München, Lichtenbergstrasse 1, 85748 Garching, Germany.
Andreas
A
Ostermann
Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0914, Japan.
Mineyuki
M
Mizuguchi
Frontier Research Center for Applied Atomic Sciences, Ibaraki University, 162-1 Shirakata, Tokai, Ibaraki 319-1106, Japan.
Nobuo
N
Niimura
Jülich Centre for Neutron Science (JCNS), Forschungszentrum Jülich GmbH Outstation at MLZ, Lichtenbergstrasse 1, 85747 Garching, Germany.
Tobias E
TE
Schrader
Frontier Research Center for Applied Atomic Sciences, Ibaraki University, 162-1 Shirakata, Tokai, Ibaraki 319-1106, Japan.
Ichiro
I
Tanaka
D003460:Crystallization / Q000379:methods*; D018360:Crystallography, X-Ray; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D051228:Geranyltranstransferase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D033363:Neutron Diffraction / Q000379:methods*; D011106:Polyisoprenyl Phosphates / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D000068296:Risedronic Acid; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism
D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D051228:Geranyltranstransferase; D000068296:Risedronic Acid; D012968:Etidronic Acid
farnesyl pyrophosphate synthase; neutron protein crystallography