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 current situation and possible future development of macromolecular crystallography are reviewed and two tendencies can be currently observed: one which treats protein crystallography as a highly automatic tool for investigating various biological problems without the need to engage in the intricacies of the technique and a second approach where this method is applied to crystals of difficult, large and complex biological systems.
Abstract: The current situation and possible future development of macromolecular crystallography are reviewed. The rapid progress and maturation of this field in recent years have to a large extent been made possible by the inspiration and generous support of several active structural genomics initiatives. Two tendencies can be currently observed: one which treats protein crystallography as a highly automatic tool for investigating various biological problems without the need to engage in the intricacies of the technique and a second approach where this method is applied to crystals of difficult, large and complex biological systems, requiring a deeper knowledge of various aspects of crystallography. In the near future it is expected that these two trends will coexist, developing in a parallel fashion.
43 citations
Cites background from "J. Appl. Cryst.の発刊に際して"
...The Rfree value (Brünger, 1992), which is based on reflections not contributing to the refinement, is much more informative and provides a more objective quality criterion than the standard R value based on all reflections, which can be easily abused (Kleywegt & Jones, 1995)....
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TL;DR: In the case of proteins, the DDQ structure-validation method is found to be very sensitive to small local errors, to omitted atoms and also to global errors in crystal structure determinations.
Abstract: Methods for the evaluation of the accuracy of crystal structures of proteins and nucleic acids are of general importance for structure–function studies as well as for biotechnological and biomedical research based upon three-dimensional structures of biomacromolecules. The structure-validation program DDQ (difference-density quality) has been developed to complement existing validation procedures. The DDQ method is based on the information present in a difference electron-density map calculated with the water molecules deliberately omitted from the structure-factor calculation. The quality of a crystal structure is reflected in this difference map by (i) the height of solvent peaks occurring at physical chemically reasonable positions with respect to protein and ligand atoms and (ii) the number and height of positive and negative `shift' peaks next to protein atoms. The higher the solvent peaks and the lower the shift peaks, the better the structure is likely to be. Moreover, extraneous positive density due to an incomplete molecular model is also monitored, since this is another indicator of imperfections in the structure. Automated analysis of these types of features in difference electron densities is used to quantify the local as well as global accuracy of a structure. In the case of proteins, the DDQ structure-validation method is found to be very sensitive to small local errors, to omitted atoms and also to global errors in crystal structure determinations.
43 citations
TL;DR: A Fortran package based on the new exact analytical methods for computing volume and surface area of overlapping spheres for computing solvation energy of proteins, the hydration effects, drug binding, molecular docking, etc., is presented.
43 citations
Cites background from "J. Appl. Cryst.の発刊に際して"
...Keywords:Solvent accessible area; Excluded volume; Proteins; Analytical equations; Stereographic projection; Fortran package; Percolati probability...
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TL;DR: BMN 673, a novel PARP1/2 inhibitor in clinical development with substantial tumor cytotoxicity, forms extensive hydrogen-bonding and π-stacking in the nicotinamide pocket, with its unique disubstituted scaffold extending towards the less conserved edges of the pocket.
Abstract: Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2), which are involved in DNA damage response, are targets of anticancer therapeutics. BMN 673 is a novel PARP1/2 inhibitor with substantially increased PARP-mediated tumor cytotoxicity and is now in later-stage clinical development for BRCA-deficient breast cancers. In co-crystal structures, BMN 673 is anchored to the nicotinamide-binding pocket via an extensive network of hydrogen-bonding and π-stacking interactions, including those mediated by active-site water molecules. The novel di-branched scaffold of BMN 673 extends the binding interactions towards the outer edges of the pocket, which exhibit the least sequence homology among PARP enzymes. The crystallographic structural analyses reported here therefore not only provide critical insights into the molecular basis for the exceptionally high potency of the clinical development candidate BMN 673, but also new opportunities for increasing inhibitor selectivity.
43 citations
Cites methods from "J. Appl. Cryst.の発刊に際して"
...The structure of the catPARP1–BMN 673 complex was solved by molecular replacement using published catPARP1 structures (PDB entries 1uk0 and 3l3m; Kinoshita et al., 2004; Penning et al., 2010) as search models using Phaser (McCoy et al., 2007)....
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Stony Brook University1, Brookhaven National Laboratory2, Nanjing University3, Binghamton University4, Universidade Federal de Minas Gerais5, Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior6, City University of New York7, Saint Joseph's College8, University at Buffalo9, Florida Atlantic University10
TL;DR: A method is presented for screening fragment libraries using acoustic droplet ejection to co-crystallize proteins and chemicals directly on micromeshes with as little as 2.5 nl of each component.
Abstract: Acoustic droplet ejection (ADE) is a powerful technology that supports crystallographic applications such as growing, improving and manipulating protein crystals. A fragment-screening strategy is described that uses ADE to co-crystallize proteins with fragment libraries directly on MiTeGen MicroMeshes. Co-crystallization trials can be prepared rapidly and economically. The high speed of specimen preparation and the low consumption of fragment and protein allow the use of individual rather than pooled fragments. The Echo 550 liquid-handling instrument (Labcyte Inc., Sunnyvale, California, USA) generates droplets with accurate trajectories, which allows multiple co-crystallization experiments to be discretely positioned on a single data-collection micromesh. This accuracy also allows all components to be transferred through small apertures. Consequently, the crystallization tray is in equilibrium with the reservoir before, during and after the transfer of protein, precipitant and fragment to the micromesh on which crystallization will occur. This strict control of the specimen environment means that the crystallography experiments remain identical as the working volumes are decreased from the few microlitres level to the few nanolitres level. Using this system, lysozyme, thermolysin, trypsin and stachydrine demethylase crystals were co-crystallized with a small 33-compound mini-library to search for fragment hits. This technology pushes towards a much faster, more automated and more flexible strategy for structure-based drug discovery using as little as 2.5 nl of each major component.
43 citations
Cites background from "J. Appl. Cryst.の発刊に際して"
...…fUniversidade Federal de Minas Gerais, 6627 Av. Antonio Carlos, 31270-901 Belo Horizonte-MG, Brazil, gCenter for Developmental Neuroscience and Department of Biology, College of Staten Island, The City University of New York, 2800 Victory Boulevard, Staten Island, NY 10314, USA, hSt Joseph’s…...
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...Crystallization is often automated, but crystal harvesting is frequently manual and laborious, although it can also be automated (Cipriani et al., 2012; Soares et al., 2011; Viola et al., 2007)....
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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.
34,239 citations
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.
28,425 citations
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'.
27,505 citations
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.
18,531 citations
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