Neutron Diffraction Analysis of Human Farnesyl Pyrophosphate Synthase in Complex with Bisphosphonate

2015 Fiscal Year Final Research Report

• Project/Area Number: 25860022
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Physical pharmacy
• Research Institution: University of Toyama
• Principal Investigator: Yokoyama Takeshi 富山大学, 医学薬学研究部(薬学), 助教 (50524162)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 構造生物学 / 中性子結晶構造解析 / 医薬品化学 / 構造活性相関 / プロトン化状態 / pH / リン酸基 / ビスホスホネート

Outline of Final Research Achievements

Neutron crystal structure of human farnesyl pyrophosphate synthase (FPPS) in complex with risedronate (RIS) was determined, and the protonation state and hydration of RIS were elucidated. The structural analysis revealed that the phosphate groups of RIS were fully deprotonated with the abnormally decreased pKa. In addition, it was suggested that the roles of E93 and D264 consisted of canceling the extra negative charges upon the binding of ligands. This information would be helpful for the development of non-bisphosphonate FPPS inhibitors.

Free Research Field

医歯薬学