Protonation State and Hydration of Bisphosphonate Bound to Farnesyl Pyrophosphate Synthase

Takeshi Yokoyama; Mineyuki Mizuguchi; Andreas Ostermann; Katsuhiro Kusaka; Nobuo Niimura; Tabias E. Schrader; Ichiro Tanaka

doi:10.1021/acs.jmedchem.5b01147

Protonation State and Hydration of Bisphosphonate Bound to Farnesyl Pyrophosphate Synthase

Takeshi Yokoyama^*, Mineyuki Mizuguchi, Andreas Ostermann, Katsuhiro Kusaka, Nobuo Niimura, Tabias E. Schrader, Ichiro Tanaka

^*Corresponding author for this work

Structural Biology

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

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 pK_a, 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.

Original language	English
Pages (from-to)	7549-7556
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	18
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01147
State	Published - 2015/09/24

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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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.",

author = "Takeshi Yokoyama and Mineyuki Mizuguchi and Andreas Ostermann and Katsuhiro Kusaka and Nobuo Niimura and Schrader, {Tabias E.} and Ichiro Tanaka",

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

year = "2015",

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doi = "10.1021/acs.jmedchem.5b01147",

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T1 - Protonation State and Hydration of Bisphosphonate Bound to Farnesyl Pyrophosphate Synthase

AU - Yokoyama, Takeshi

AU - Mizuguchi, Mineyuki

AU - Ostermann, Andreas

AU - Kusaka, Katsuhiro

AU - Niimura, Nobuo

AU - Schrader, Tabias E.

AU - Tanaka, Ichiro

PY - 2015/9/24

Y1 - 2015/9/24

N2 - 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.

AB - 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.

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JF - Journal of Medicinal Chemistry

IS - 18

ER -

Protonation State and Hydration of Bisphosphonate Bound to Farnesyl Pyrophosphate Synthase

Abstract

ASJC Scopus subject areas

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