In:
Acta Crystallographica Section A Foundations and Advances, International Union of Crystallography (IUCr), Vol. 70, No. a1 ( 2014-08-05), p. C1220-C1220
Abstract:
Nitrogen-containing bisphosphonates (N-BPs), such as risedronate and zoledronate, are currently used as clinical drug for bone-resorption diseases and are potent inhibitor of farnesyl pyrophosphate synthase (FPPS). The potential of N-BPs as antitumor agents has also been suggested by the several in vitro and in vivo preclinical studies. However, BP drugs limit their therapeutic use to bone-related diseases, because BPs are highly charged and water soluble molecules. 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. In order to develop a novel FPPS inhibitor, the hydrogen-bond networks formed by FPPS, BPs and water molecules are necessary to be elucidated. To understand the structural characteristics of N-BPs bound to FPPS, including hydrogen 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 and 10.7% Rmerge. As a result of X-ray/neutron joint refinment, R and Rfree values for the neutron data were 19.6 and 23.3%, respectively. This neutron structure clearly reveals the protonation state of risedronate, hydration in the inhibitor-binding region. Furthermore, the amide H/D exchange analysis showed that there is a highly rigid region which regulate the structural change upon the binding of the ligands. Here we will discuss the detailed hydrogen-bond network and the protonation state of FPPS and risedronate.
Type of Medium:
Online Resource
ISSN:
2053-2733
DOI:
10.1107/S2053273314087798
Language:
Unknown
Publisher:
International Union of Crystallography (IUCr)
Publication Date:
2014
detail.hit.zdb_id:
2020844-3
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