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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.
AuthorsTakeshi Yokoyama, Mineyuki Mizuguchi, Andreas Ostermann, Katsuhiro Kusaka, Nobuo Niimura, Tabias E Schrader, Ichiro Tanaka
JournalJournal of medicinal chemistry (J Med Chem) Vol. 58 Issue 18 Pg. 7549-56 (Sep 24 2015) ISSN: 1520-4804 [Electronic] United States
PMID26314394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Bone Density Conservation Agents
  • Hemiterpenes
  • Organophosphorus Compounds
  • Protons
  • isopentenyl pyrophosphate
  • Hydrogen
  • Deuterium
  • Geranyltranstransferase
  • Magnesium
  • Risedronic Acid
Topics
  • Bone Density Conservation Agents (chemistry)
  • Crystallography, X-Ray
  • Deuterium (chemistry)
  • Geranyltranstransferase (chemistry)
  • Hemiterpenes (chemistry)
  • Hydrogen (chemistry)
  • Magnesium (chemistry)
  • Models, Molecular
  • Neutron Diffraction
  • Organophosphorus Compounds (chemistry)
  • Protein Conformation
  • Protons
  • Risedronic Acid (chemistry)

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