J. Appl. Cryst.の発刊に際して
10 Mar 1970-Vol. 12, Iss: 1, pp 1-1
About: The article was published on 1970-03-10 and is currently open access. It has received 8159 citations till now.
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TL;DR: The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library and a first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds.
Abstract: The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on a Biacore™ T100 against p38α and two selectivity targets. A sub-set of our library was the focus of detailed follow-up analyses that included hit confirmation, affinity determination on 24 confirmed, selective hits and competition assays of these hits with respect to a known ATP binding site inhibitor. In addition, functional activity against p38α was assessed in a biochemical assay using a mobility shift platform (LC3000, Caliper LifeSciences). A selection of fragments was also evaluated using fluorescence lifetime (FLEXYTE™) and microscale thermophoresis (Nanotemper) technologies. A good correlation between the data for the different assays was found. Crystal structures were solved for four of the small molecules complexed to p38α. Interestingly, as determined both by X-ray analysis and SPR competition experiments, three of the complexes involved the fragment at the ATP binding site, while the fourth compound bound in a distal site that may offer potential as a novel drug target site. A first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds. This approach could form the basis for developing novel and active p38α inhibitors. More broadly, it illustrates the power of combining a range of biophysical and biochemical techniques to the discovery of fragments that facilitate the development of novel modulators of kinase and other drug targets.
42 citations
TL;DR: In this paper, the reaction of salicylaldehyde, o-aminophenols, and di-n -butyltin IV oxide (3) to give six di- n-butyllin IV compounds (4a, 4b, 4d and 4e) was achieved in good yields.
42 citations
TL;DR: Hydrogelation behavior of two amino-terpyridine ligands in the presence of divalent metal ions in water was studied in detail and the effect of ligand structure and different counter anions on the gel morphologies was explored.
Abstract: Hydrogelation behavior of two amino-terpyridine ligands in the presence of divalent metal ions in water was studied in detail. The effect of ligand structure and different counter anions on the gel morphologies was also explored.
42 citations
TL;DR: The lattice energies of the four methyl paraben structures have been calculated with a range of methods based on ab initio electronic calculations on either the crystal or single molecule shows that the differences in the induction energy of the different hydrogen-bonded chain geometries have a significant effect on relative lattices energies, but that conformational energy, repulsion, dispersion, and electrostatic also contribute.
Abstract: Four polymorphic forms of methyl paraben (methyl 4-hydroxybenzoate, 1), denoted 1-I (melting point 126 °C), 1-III (109 °C), 1-107 (107 °C), and 1-112 (112 °C), have been investigated by thermomicroscopy, infrared spectroscopy, and X-ray crystallography. The crystal structures of the metastable forms 1-III, 1-107, and 1-112 have been determined. All polymorphs contain the same O–H···O═C connected catemer motif, but the geometry of the resulting H-bonded chain is different in each form. The Z′ = 3 structure of 1-I (stable form; space group Cc) contains local symmetry elements. The crystal packing of each of the four known crystal structures of 1 was compared with the crystal structures of 12 chemical analogues. Close two-dimensional relationships exist between 1-112 and a form of methyl 4-aminobenzoate and between 1-107 and dimethyl terephthalate. The lattice energies of the four methyl paraben structures have been calculated with a range of methods based on ab initio electronic calculations on either the c...
42 citations
TL;DR: The use of two different classes of compounds (monovalent and polyvalent cations) that can be successfully utilized in the quick cryosoaking procedure for the derivatization and phasing of protein crystals is described.
Abstract: The preparation of derivatives by the traditional methods of soaking is one of the most time-consuming steps in protein crystal structure solution by X-ray diffraction techniques. The `quick cryosoaking' procedure for derivatization with halides (monovalent anions) offers the possibility of significantly speeding up this process [Dauter et al. (2000), Acta Cryst. D56, 232–237]. In the present work, an extension of this technique is proposed and the use of two different classes of compounds (monovalent and polyvalent cations) that can be successfully utilized in the quick cryosoaking procedure for the derivatization and phasing of protein crystals is described. This approach has been tested on hen egg-white lysozyme and has been successfully used to solve the structure of a novel trypsin inhibitor. The possibility of using cations in the fast cryosoaking procedure gives additional flexibility in the process of derivatization and increases the chances of success in phase determination. This method can be applied to high-throughput crystallographic projects.
42 citations
Cites methods from "J. Appl. Cryst.の発刊に際して"
...A total of 500 diffE values (Blessing & Smith, 1999) were used to generate 5000 triple invariants....
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...Scaled intensities for each derivative were submitted to SnB 2.1 (Weeks & Miller, 1999), where normalized anomalous differences (diffE) were calculated with the program DREAR (Blessing & Smith, 1999)....
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References
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TL;DR: The goals of the PDB are described, the systems in place for data deposition and access, how to obtain further information and plans for the future development of the resource are described.
Abstract: The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
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TL;DR: New features added to the refinement program SHELXL since 2008 are described and explained.
Abstract: The improvements in the crystal structure refinement program SHELXL have been closely coupled with the development and increasing importance of the CIF (Crystallographic Information Framework) format for validating and archiving crystal structures. An important simplification is that now only one file in CIF format (for convenience, referred to simply as `a CIF') containing embedded reflection data and SHELXL instructions is needed for a complete structure archive; the program SHREDCIF can be used to extract the .hkl and .ins files required for further refinement with SHELXL. Recent developments in SHELXL facilitate refinement against neutron diffraction data, the treatment of H atoms, the determination of absolute structure, the input of partial structure factors and the refinement of twinned and disordered structures. SHELXL is available free to academics for the Windows, Linux and Mac OS X operating systems, and is particularly suitable for multiple-core processors.
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TL;DR: CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics.
Abstract: CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics. The map-fitting tools are available as a stand-alone package, distributed as `Coot'.
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TL;DR: The PHENIX software for macromolecular structure determination is described and its uses and benefits are described.
Abstract: Macromolecular X-ray crystallography is routinely applied to understand biological processes at a molecular level. However, significant time and effort are still required to solve and complete many of these structures because of the need for manual interpretation of complex numerical data using many software packages and the repeated use of interactive three-dimensional graphics. PHENIX has been developed to provide a comprehensive system for macromolecular crystallographic structure solution with an emphasis on the automation of all procedures. This has relied on the development of algorithms that minimize or eliminate subjective input, the development of algorithms that automate procedures that are traditionally performed by hand and, finally, the development of a framework that allows a tight integration between the algorithms.
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TL;DR: A description is given of Phaser-2.1: software for phasing macromolecular crystal structures by molecular replacement and single-wavelength anomalous dispersion phasing.
Abstract: Phaser is a program for phasing macromolecular crystal structures by both molecular replacement and experimental phasing methods. The novel phasing algorithms implemented in Phaser have been developed using maximum likelihood and multivariate statistics. For molecular replacement, the new algorithms have proved to be significantly better than traditional methods in discriminating correct solutions from noise, and for single-wavelength anomalous dispersion experimental phasing, the new algorithms, which account for correlations between F+ and F−, give better phases (lower mean phase error with respect to the phases given by the refined structure) than those that use mean F and anomalous differences ΔF. One of the design concepts of Phaser was that it be capable of a high degree of automation. To this end, Phaser (written in C++) can be called directly from Python, although it can also be called using traditional CCP4 keyword-style input. Phaser is a platform for future development of improved phasing methods and their release, including source code, to the crystallographic community.
17,755 citations