scholarly journals Crystallization and preliminary neutron diffraction experiment of human farnesyl pyrophosphate synthase complexed with risedronate

2014 ◽  
Vol 70 (4) ◽  
pp. 470-472 ◽  
Author(s):  
Takeshi Yokoyama ◽  
Andreas Ostermann ◽  
Mineyuki Mizuguchi ◽  
Nobuo Niimura ◽  
Tobias E. Schrader ◽  
...  
Keyword(s):  
Neutron Diffraction ◽  
Structural Characteristics ◽  
Water Molecules ◽  
Farnesyl Pyrophosphate ◽  
Neutron Diffraction Experiment ◽  
Neutron Data ◽  
Farnesyl Pyrophosphate Synthase ◽  
X Ray ◽  
Complex Crystals ◽  
Clinical Drug

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 mm3) 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.

About the degree of hydration in potassiumtrisoxalatochromate hydrate

2005 ◽  
Vol 220 (11) ◽  
Author(s):  
Chunhua Hu ◽  
Gernot Heger ◽  
Irmgard Kalf ◽  
Ullrich Englert
Keyword(s):  
Neutron Diffraction ◽  
Water Molecules ◽  
Structure Model ◽  
Hydrogen Atoms ◽  
Neutron Data ◽  
X Ray ◽  
Degree Of Hydration ◽  
Thermogravimetric Data ◽  
Hydration Model ◽  
Good Agreement

AbstractData obtained from single crystal X-ray and neutron diffraction experiments have been combined with results from thermogravimetry in order to derive an improved structure model for potassium tris(oxalato)chromate hydrate. The degree of hydration for this compound has been reinvestigated: Earlier work assumed a trihydrate stoichiometry and had to accept an unusually short K···O distance of 2.3 Å. Our neutron data reveal the position of the hydrogen atoms in the water molecules; they prove that abnormally short separations between a cation and atoms of a water molecule can only occur between sites of mutually exclusive occupancy and hence remain without chemical relevance. Closest K···O distances in our revised hydration model amount to 2.6 Å, in good agreement with expectation. Both diffraction experiments and thermogravimetric data agree with the stoichiometry K

The water molecules in CuSO 4 .5H 2 O

1962 ◽  
Vol 266 (1324) ◽  
pp. 95-108 ◽  
Keyword(s):  
Hydrogen Bonds ◽  
Neutron Diffraction ◽  
Single Crystals ◽  
Water Molecules ◽  
X Ray Diffraction ◽  
Neutron Data ◽  
X Ray ◽  
Atomic Nuclei ◽  
Different Temperatures ◽  
Molecular Rotations

Single crystals of fully hydrated copper sulphate have been studied by neutron diffraction and the measurements have been used to construct projections of the neutron-scattering density, due to the atomic nuclei, on the three crystallographic axial planes. These provide full details of the shape and environment of the water molecules and of the hydrogen bonds which link together the atoms in the structure, which was originally proposed by Beevers & Lipson as a result of X -ray diffraction work. It is found that the H—O—H angles for all the water molecules are within a degree or two of the tetrahedral value and the hydrogen bonds have to be bent by up to 26° in order to accommodate them. Corresponding measurements have been made at a series of five different temperatures between 20 and 90°C in order to test a suggestion that molecular rotations of the water molecules occurred before the onset of dehydration: the neutron data refute this suggestion.

scholarly journals Neutron crystal structure of human FPPS complexed with risedronate

2014 ◽  
Vol 70 (a1) ◽  
pp. C1220-C1220
Author(s):  
Takeshi Yokoyama ◽  
Andreas Ostermann ◽  
Mineyuki Mizuguchi ◽  
Nobuo Niimura ◽  
Tobias Schrader ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Neutron Diffraction ◽  
Antitumor Agents ◽  
Structural Characteristics ◽  
Water Soluble ◽  
Water Molecules ◽  
Protonation State ◽  
Hydrogen Atoms ◽  
X Ray ◽  
Hydrogen Bond Networks

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 mm3) 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.

scholarly journals Lower resolution Laue neutron data yield correct nanocluster formulations

2014 ◽  
Vol 70 (a1) ◽  
pp. C187-C187
Author(s):  
Alison Edwards
Keyword(s):  
Neutron Diffraction ◽  
Single Crystal ◽  
Diffraction Pattern ◽  
Precise Determination ◽  
Data Sets ◽  
X Rays ◽  
Low Resolution ◽  
Neutron Data ◽  
X Ray ◽  
Product Formulation

"The renaissance in Laue studies - at neutron sources - provides us with access to single crystal neutron diffraction data for synthetic compounds without requiring synthesis of prohibitively large amounts of compound or improbably large crystals. Such neutron diffraction studies provide vital data where proof of the presence or absence of hydrogen in particular locations is required and which cannot validly be proved by X-ray studies. Since the commissioning of KOALA at OPAL in 2009[1] we have obtained numerous data sets which demonstrate the vital importance of measuring data even where the extent of the diffraction pattern is at relatively low resolution - especially when compared to that obtainable for the same compound with X-rays. In the Laue experiment performed with a fixed radius detector, data reduction is only feasible for crystals in the ""goldilocks"" zone – where the unit cell is relatively large for the detector, a correspondingly low resolution diffraction pattern in which adjacent spots are less affected by overlap will yield more data against which a structure can be refined than a pattern of higher resolution – one where neighbouring spots overlap rendering both unusable (in our current methodology). Analogous application of powder neutron diffraction in such determinations is also considered. Single crystal neutron diffraction studies of several important compounds (up to 5KDa see figure below)[2] in which precise determination of hydride content by neutron diffraction was pivotal to the final formulation will be presented. The neutron data sets typically possess 20% or fewer unique data at substantially "lower resolution" than the corresponding X-ray data sets. Careful refinement clearly reveals chemical detail which is typically unexplored in related X-ray diffraction studies reporting high profile chemistry despite the synthetic route being one which hydride ought to be considered/excluded in product formulation."

Zeolite Rho Loaded with Methylamines. III. Trimethylamine Loadings

1997 ◽  
Vol 53 (3) ◽  
pp. 444-450 ◽  
Author(s):  
C. Weidenthaler ◽  
R. X. Fischer ◽  
L. Abrams ◽  
A. Hewat
Keyword(s):  
Data Collection ◽  
Neutron Diffraction ◽  
Diffraction Analysis ◽  
Room Temperature ◽  
Methyl Groups ◽  
Neutron Data ◽  
Rietveld Refinements ◽  
X Ray ◽  
Deuterated Sample ◽  
Zeolite Rho

Samples of two differently prepared zeolites rho loaded with different amounts of trimethylamine (TMA) were studied in their hydrated and dehydrated forms by X-ray and neutron diffraction experiments. Both zeolites are partially dealuminated, as indicated by nonframework Al, which is assumed to be Al2O3 or AlOOH. Series I was prepared from dry-calcined NHn-rho at 873 K, series II from steam-calcined NHn-rho at 773 K. The samples were loaded with different amounts of deuterated TMA. Rietveld refinements yielded the following results for series I: (1) H3.8(H-TMA)5Cs0.2Al9 Si39O96.Al2O3.22H2O, X-ray data collection at room temperature, Im\overline 3m, a = 15.0542 (2) Å, R wp = 0.094; (2) composition as in (1) (anhydrous), neutron data collection at 5 K of dehydrated and deuterated sample, Im3m, a = 15.0467 (4) Å, R wp = 0.034. Series II: (3) H0.3(H-TMA)5Cs0.7Al6Si42O96.2.5Al2O3.22H2O, X-ray data collection at room temperature, Im\overline 3m, a = 15.0574 (2) Å, R wp = 0.118; (4) composition as in (3) (anhydrous), neutron data collection at 5 K of dehydrated and deuterated sample, lm\overline 3m, a = 15.0761 (5) Å, R wp = 0.037. In all determinations the TMA molecules reside with the N and H (D in neutron diffraction analysis) atoms on the central axes (x, 0, 0) pointing towards the center of the single eight-ring, whilst the three methyl groups point away to the center of the \alpha-cage.

Neutron diffraction experiment with the Y116S variant of transthyretin using iBIX at J-PARC: application of a new integration method

2020 ◽  
Vol 76 (11) ◽  
pp. 1050-1056
Author(s):  
Katsuhiro Kusaka ◽  
Takeshi Yokoyama ◽  
Taro Yamada ◽  
Naomine Yano ◽  
Ichiro Tanaka ◽  
...  
Keyword(s):  
Neutron Diffraction ◽  
Diffraction Data ◽  
Amyloid Fibrils ◽  
Integration Method ◽  
Proton Accelerator ◽  
Diffraction Experiment ◽  
Wild Type ◽  
Neutron Diffraction Experiment ◽  
X Ray ◽  
Attr Amyloidosis

Transthyretin (TTR) is one of more than 30 amyloidogenic proteins, and the amyloid fibrils found in patients afflicted with ATTR amyloidosis are composed of this protein. Wild-type TTR amyloids accumulate in the heart in senile systemic amyloidosis (SSA). ATTR amyloidosis occurs at a much younger age than SSA, and the affected individuals carry a TTR mutant. The naturally occurring amyloidogenic Y116S TTR variant forms more amyloid fibrils than wild-type TTR. Thus, the Y116S mutation reduces the stability of the TTR structure. A neutron diffraction experiment on Y116S TTR was performed to elucidate the mechanism of the changes in structural stability between Y116S variant and wild-type TTR through structural comparison. Large crystals of the Y116S variant were grown under optimal crystallization conditions, and a single 2.4 mm3 crystal was ultimately obtained. This crystal was subjected to time-of-flight (TOF) neutron diffraction using the IBARAKI biological crystal diffractometer (iBIX) at the Japan Proton Accelerator Research Complex, Tokai, Japan (J-PARC). A full data set for neutron structure analysis was obtained in 14 days at an operational accelerator power of 500 kW. A new integration method was developed and showed improved data statistics; the new method was applied to the reduction of the TOF diffraction data from the Y116S variant. Data reduction was completed and the integrated intensities of the Bragg reflections were obtained at 1.9 Å resolution for structure refinement. Moreover, X-ray diffraction data at 1.4 Å resolution were obtained for joint neutron–X-ray refinement.

The Crystal and Molecular Structure of Chloro-mer-Tris(dimethylphenylphosphine)-cis-dihydridoiridium(III) by X-Ray and Neutron Diffraction

1988 ◽  
Vol 41 (5) ◽  
pp. 641 ◽  
Author(s):  
GB Robertson ◽  
PA Tucker
Keyword(s):  
Molecular Structure ◽  
Neutron Diffraction ◽  
Single Crystal ◽  
Least Squares ◽  
Crystal And Molecular Structure ◽  
Monoclinic Space Group ◽  
Neutron Data ◽  
Full Matrix ◽  
Space Group ◽  
X Ray

The structure of mer-(Pme2Ph)3Cl-cis-H2IrIII (1) has been determined by single-crystal X-ray and neutron diffraction analyses. Crystals are monoclinic, space group P21, with a 11.476(4), b 14.069(5), c 8.286(3)Ǻ, β 92.45(1)° and Z 2. Full-matrix least-squares analyses converged 0.022 for 7773 X-ray data and R(F2) = 0.062 for 1538 neutron data. Ir -H [1.557(11)Ǻ trans to Cl, 1.603(10) Ǻ trans to P] and Ir -P distances [2.292(1)Ǻ trans to P, 2.328(1)Ǻ trans to H] both exhibit trans lengthening effects. Consistent with the increased hydride content the Ir -P distances in (1) are c. 0.04 Ǻ shorter than for the corresponding bonds in its dichloro monohydrido analogues and c. 0.08 Ǻ shorter than those in the trichloride . In contrast Ir-Cl [2.505(1)Ǻ] is not significantly different to the corresponding distance (2.504 Ǻ av.) in mer -(PMe2Ph)3-cis-Cl2HIrIII.

Unambiguous determination of H-atom positions: comparing results from neutron and high-resolution X-ray crystallography

2010 ◽  
Vol 66 (5) ◽  
pp. 558-567 ◽  
Author(s):  
Anna S. Gardberg ◽  
Alexis Rae Del Castillo ◽  
Kevin L. Weiss ◽  
Flora Meilleur ◽  
Matthew P. Blakeley ◽  
...  
Keyword(s):  
Neutron Diffraction ◽  
Electron Density ◽  
Pyrococcus Furiosus ◽  
X Ray Diffraction ◽  
Neutron Data ◽  
X Ray ◽  
X Ray Crystallography ◽  
Density Maps ◽  
Improved Model

The locations of H atoms in biological structures can be difficult to determine using X-ray diffraction methods. Neutron diffraction offers a relatively greater scattering magnitude from H and D atoms. Here, 1.65 Å resolution neutron diffraction studies of fully perdeuterated and selectively CH3-protonated perdeuterated crystals ofPyrococcus furiosusrubredoxin (D-rubredoxin and HD-rubredoxin, respectively) at room temperature (RT) are described, as well as 1.1 Å resolution X-ray diffraction studies of the same protein at both RT and 100 K. The two techniques are quantitatively compared in terms of their power to directly provide atomic positions for D atoms and analyze the role played by atomic thermal motion by computing the σ level at the D-atom coordinate in simulated-annealing composite D-OMIT maps. It is shown that 1.65 Å resolution RT neutron data for perdeuterated rubredoxin are ∼8 times more likely overall to provide high-confidence positions for D atoms than 1.1 Å resolution X-ray data at 100 K or RT. At or above the 1.0σ level, the joint X-ray/neutron (XN) structures define 342/378 (90%) and 291/365 (80%) of the D-atom positions for D-rubredoxin and HD-rubredoxin, respectively. The X-ray-only 1.1 Å resolution 100 K structures determine only 19/388 (5%) and 8/388 (2%) of the D-atom positions above the 1.0σ level for D-rubredoxin and HD-rubredoxin, respectively. Furthermore, the improved model obtained from joint XN refinement yielded improved electron-density maps, permitting the location of more D atoms than electron-density maps from models refined against X-ray data only.

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