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International Union of Crystallography

The IUCr is an International Scientific Union. Its objectives are to promote international cooperation in crystallography and to contribute to all aspects of crystallography, to promote international publication of crystallographic research, to facilitate standardization of methods, units, nomenclatures and symbols, and to form a focus for the relations of crystallography to other sciences.

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Fluctuation X-ray scattering

In biology, materials science and the energy sciences, structural information provides important insightsdc5005 into the understanding of matter. The link between a structure and its properties can suggest new avenues for designed improvements of synthetic materials or provide new fundamental insights in biology and medicine at the molecular level.

During standard X-ray solution scattering experiments, molecules tumble around during X-ray exposures, resulting in an angularly isotropic diffraction pattern because of the full orientational averaging of the molecules that scatter X-rays. When X-ray snapshots are collected at timescales shorter than a few nanoseconds, such that molecules are virtually frozen in space and time during the scattering experiment, X-ray diffraction patterns are obtained that are no longer angularly isotropic. These measurements, called fluctuation X-ray scattering, are typically performed on an X-ray free electron laser or on an ultra-bright synchrotron and can provide fundamental insights into the structure of biological molecules, engineered nanoparticles or energy-related mesoscopic materials not attainable via standard scattering methods. 

A group of scientists from the Lawrence Berkeley National Laboratory [Malmerberg et al., (2015), IUCrJ, 2, doi:10.1107/S2052252515002535] recently presented an intuitive view of the nature of fluctuation X-ray scattering data and their properties. The scientists have shown that fluctuation scattering is a natural extension of traditional small-angle X-ray scattering and that a number of fundamental operational properties translate from small- and wide-angle X-ray scattering into fluctuation scattering. The authors also show that even with a fairly limited fluctuation scattering dataset, the amount of recoverable structural detail is greatly increased compared with what can be obtained from standard SAXS/WAXS experiments. Given that the high-quality structural models can be obtained from fluctuation scattering data and the ever-increasing availability of X-ray sources at which these experiments can be performed, the researchers expect that fluctuation scattering experiments will become routine in the future.

”Although fluctuation scattering experiments are not standard or routine at the moment, this work enables us to assess the quality of experimental data and allows us to validate our experimental protocols and data reduction routines”, Peter Zwart says.

Posted 25 Mar 2015 

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Biochemistry researchers at the University of Oxford share their work with the public in crystallography's centenary year

garman5_200px.jpgX-ray crystallography has never had so prominent a place in the world. The illustrious history of the field and its discoveries were celebrated by numerous events across the UK and elsewhere during 2014, the International Year of Crystallography, www.iycr2014.org. Researchers from the Department of Biochemistry at the University of Oxford participated in several of these events.

Jointly organised by the IUCr and UNESCO, the year commemorated the centennial of the birth of X-ray crystallography, thanks to the work of Max von Laue and the Braggs father and son.

The award of the Nobel Prize to Max von Laue in 1914 recognised his work on copper sulphate crystals. He was the first person to discover that X-rays can be diffracted by crystals and observed the characteristic spots from these crystals.

Taking the work a step further, William and Lawrence Bragg discovered that X-rays could be used to determine the positions of atoms within crystals accurately. By formulating "Bragg’s Law", they gave researchers the tool to interpret the diffraction pattern of spots and generate a detailed picture of the three-dimensional structure of compounds. They received a Nobel Prize for this achievement in 1915.

The International Year of Crystallography aimed to mark these and many other milestones in the field, from the discovery of the DNA double helix to groundbreaking work on graphene and the ribosome complex (around 280,000 non-hydrogen atoms). Through an incredible variety of activities including science fairs, exhibitions and professional-level training sessions, crystallography has been brought to life for many different audiences.

Several crystallography researchers from the Biochemistry department contributed to events marking ajonnybb century of crystallography; these included Professor Elspeth Garman; Jonny Brooks-Bartlett, a DPhil student in Elspeth's group; Associate Professor Matt Higgins; Professor Judy Armitage and Professor Mark Sansom.

Talking to a reporter Professor Garman comments, "The year has really raised the profile of the topic internationally and has resulted in lots of outreach and public engagement activities. There is a new energy and it has really benefited countries where there are limited activities in the field. Some of the initiatives will undoubtedly be continued".

This press release is reprinted from material taken from the Department of Biochemistry website at the University of Oxford. The link to the original press release can be found here.

Posted 19 Mar 2015 

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The ecstasy and the agony: compression studies of MDMA

ps5039MDMA (3,4-methyenedioxymethamphetamine), a Class A substance that is usually found in a tableted form, is a psychoactive drug which is structurally similar to methylamphetamine and acts as a central nervous system stimulant, producing mood enhancement, increased energy and other empathetic effects. MDMA was first synthesized by Merck as far back as 1912 as a potential appetite suppressant; however, the company never marketed it as such.

In the 1970s and 1980s the substance surfaced on the recreational drug scene and its widespread abuse led many countries to prohibit the possession, supply and manufacture of MDMA. Currently, in the UK, MDMA is controlled as a Class A, Schedule 1 substance owing to its illicit use as a recreational drug, and its implication in a number of highly publicized fatalities. It is usually found in tableted form; the tableting procedure subjects the material to elevated pressures in which conversion to other polymorphs may occur.

A group of scientists from Glasgow, Dundee and Manchester decided to investigate how MDMA behaves under such extreme pressure [Connor et al. (2015). Acta Cryst. B71, 3-9; doi:10.1107/S2052520614026389]

Under ambient conditions MDMA is only observed in one orthorhombic polymorph. The scientists found there was no change in polymorph even to extremely high pressures, i.e. it is very unlikely that, if starting with this form of MDMA, a polymorphic transition would occur during tableting.

The scientists mention that, owing to this being a single crystal study and the fact that pressure needed to be applied hydrostatically to the sample to obtain the 3-D information on the structure, one may find under non-hydrostatic conditions that a polymorphic change may indeed occur.

The scientists intend to keep investigating illicit materials under various conditions of pressure and temperature to gain a better understanding of their solid-state chemistry.

Posted 17 Mar 2015

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Microbial soil cleanup at Fukushima

Proteins from salt-loving, halophilic, microbes could be the key to cleaning up leaked radioactive strontiummn5080 and caesium ions from the Fukushima Dai-ichi Nuclear Power Plant incident in Japan. The publication of the X-ray structure of a beta-lactamase enzyme from one such microbe, the halophile Chromohalobacter sp. 560, reveals it to have highly selective cesium binding sites.

A collaboration between researchers at the Japan Atomic Energy Agency in Tokai, Ibaraki, Kyushu Synchrotron Light Research Center in Saga, Kagoshima University, and Florida State University, Tallahassee, USA, has led to a 1.8 to 2.9 angstrom resolution structure for this enzyme. Anomalous X-ray diffraction also revealed binding sites in the protein for Sr2+ and Cs+ ions, the team reports [Arai et al. (2015). Acta Cryst. D71, 541-554; DOI: 10.1107/S1399004714027734].

The team demonstrated how they could locate caesium ions in a specific site within the protein even in the presence of a nine-fold molar excess of sodium ions, which would normally out-compete any binding site. Intriguingly, the presence of strontium and caesium ions does not diminish the activity of the enzyme determined using isothermal titration calorimetry. "The observation of a selective and high-affinity caesium-binding site provides important information that is useful for the design of artificial caesium-binding sites that may be useful in the bioremediation of radioactive isotopes," the team explains.

It is well known that proteins from halophilic bacteria have an abundance of acidic amino acids and so present an acidic surface that can interact with a range of metal ions. There are twelve types of such enzymes recorded in the Protein Data Bank that can bind to sodium, magnesium, potassium, calcium, iron, zinc, strontium and cadmium ions. Indeed, the presence of these materials in various enzymes is usually a prerequisite for their structure and functionality. Because of this metal affinity, the team reasoned that proteins from halophiles might be useful as molecular mops for separating precious metals from mixtures or in remediation when toxic metals ions must be extracted selectively from a site. More specifically, the proteins could act as models for artificial reagents to be used in this context.

With respect to the Fukushima incident, the team explains that most of the radioactive caesium was deposited on the land at the site. Amounting to 2.4 petabequerels (PBq) of radioactivity and it is fixed in soil particles, comprising weathered biotite, a micaceous mineral found in many igneous and metamorphic rocks. Much of the soil has been removed, but the issue of extracting the radioactive elements for safe disposal has not been addressed. Moreover, the soil that remains at the site is also contaminated and no cost-effective method for extracting the caesium that leeches from it into the environment has been demonstrated.

The team suggests that protein absorbents related to the beta-lactamase from Chromohalobacter might be designed using the techniques of synthetic biology, the most likely approach being to engineer a native protein to make the affinity site described by the team. The genes for such an agent might then be engineered into new breeds of plant that could be grown on the site. With the protein absorbents expressed in plant roots, caesium could be extracted from the soil efficiently, the plants harvested and their new radioactive cargo disposed of safely, leaving behind improved soil.

"Although the removal of caesium is an important theme for us, public acceptance for the use of genetically engineered plants is not strong enough here in Japan, so we are going to shift our theme for finding useful sites to gather other rare materials using engineered proteins derived from the structural information of the halophilic proteins," team member Ryota Kuroki revealed to us.
Posted 10 Mar 2015 

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Smart crystallization

bw5424A novel nucleating agent that builds on the concept of molecularly imprinted polymers (MIPs) could allow crystallographers access to proteins and other biological macromolecules that are usually reluctant to form crystals. The semi-liquid non-protein agent is reported by UK scientists [Khurshid et al. (2015). Acta Cryst. D71, 534-540; doi: 10.1107/S1399004714027643].

Sahir Khurshid, Lata Govada and Naomi Chayen of Computational and Systems Medicine at Imperial College London, working with chemists Hazim EL-Sharif and Subrayal Reddy of the University of Surrey, Guildford, explain how they have modified MIPs to give the agents a texture suitable for high-throughput trials. Their work shows improvement in crystal quality for those macromolecules that were known to be crystallizable but also boosts the probability of success when they screen for suitable crystallization conditions for more intractable proteins. The team describes the application of these materials as "simple and time-efficient" as well as offering structural biologists a new and potent tool for crystallization trials.

In some sense protein crystallography has stagnated for at least a decade in terms of the success rate in obtaining diffraction-quality, purified crystals. Just one in five protein targets have succumbed during this time. As such, crystallographers have been hunting for agents that could be used to seed crystal growth and make available some of the most important membrane proteins and other biological macromolecules of interest to biomedical scientists and drug developers. Various novel seeding protocols and some nucleating agents have proven useful. However, to be more widely adopted and adapted, Khurshid and colleagues suggest that novel agents must be amenable to high-throughput crystallography applications whilst preferably being non-protein.

In 2011, the team reported that MIPs, which they dubbed "smart materials”, could be used to nucleate crystallization of proteins. The MIPs based on polyacrylamide are synthesized in the presence of a template molecule in solution and a cross-linker reagent. Removal of the template - the protein of interest - after completion of the cross-linking step leaves behind a polymer shell with "ghost sites" containing a fingerprint of the protein. The protein can then be reintroduced under crystallization conditions and so the polymer acts as a support around which the protein might crystallize. At the time, they demonstrated proof of principle with nine proteins. Originally, the team thought that they would need a new MIP for each protein they wished to crystallize but this turned out not to be the case. A single MIP template on one protein could act as a nucleating agent for other proteins of similar molecular weight.

The original MIP agents are gel-like materials, which makes them difficult to manipulate in a high-throughput system, because being viscous they cause blockages in robotic dispensing tips and other figurative bottlenecks in the equipment. An alternative approach might have been to suspend them in a solvent, but this brings its own problems. Instead, the team’s current work has now developed a less viscous - close to that of low molecular weight polyethylene glycol (PEG) - generic MIP that can trap and nucleate different proteins with similar hydrodynamic radii.

The team has now tested their modified MIP agent with six proteins, among them thaumatin (from Thaumatococcus daniellii), bovine pancreatic trypsin, lysozyme (from hen-egg white) and bovine haemoglobin. They then used target proteins, e.g. human macrophage migration inhibitory factor and since publication, a complex of an antibody with a fragment of the CCR5 receptor for the automated optimization trials with the templated MIPs. The agents can be stored at 4 °C for several weeks and only require vortexing if unused to make them "active" again.

"Having patented the design and application of MIPs for crystallization, and validated the modified MIPs for high-throughput trials, the way is now paved for commercialization," the team says.

Posted 02 Mar 2015 

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Radiation damage to macromolecules: kill or cure?

RD8Radiation damage induced by X-ray beams during macromolecular diffraction experiments remains an issue of concern in structural biology. While advances in our understanding of this phenomenon, driven in part by a series of workshops in this area, undoubtedly have been and are still being made, there are still questions to be answered.

Interest in radiation damage to macromolecules during structural experiments has not abated over the last few years, since there remains a need to understand both the parameters that affect radiation damage progression (the ‘kill’) and also the artifacts produced by it. Although there is now a growing body of literature pertaining to this topic (see for example the special issues of the Journal of Synchrotron Radiation arising from papers presented at the 2nd to 7th International Workshops on Radiation Damage to Biological Crystalline Samples, published in 2002, 2005, 2007, 2009, 2011 and 2013, respectively), clear foolproof methods for experimenters to routinely minimize damage have yet to emerge. Additionally, radiation damage is also a concern and limiting problem in other methods used in structural biology such as electron microscopy, SAXS and scanning X-ray diffraction. However, the recently available free electron lasers (FELs) have presented the possibility and promise that samples will give ‘diffraction before destruction’: is this indeed the ‘cure’ for the challenges of radiation damage?

For the majority of macromolecular crystallographers, using a FEL is not yet a realistic expectation. For them, radiation damage to their samples is likely to become an increasingly observed phenomenon, since much smaller X-ray beams with very high flux densities are becoming available due to upgrades in both electron storage rings and the synchrotrons that feed them. These fourth-generation synchrotrons are engendering even more interest in research into radiation damage and its deleterious effects.

It is clear from a special issue devoted to radiation damage [Garman, E. F. and Weik, M. (2015). J. Synchrotron Rad. 22] that there remains much scope for further studies to inform both experimental practice and the interpretation of the resulting structures so that radiation damage can become a widely recognised and understood facet of structural biology. These experiments on macromolecular crystals will certainly involve more ‘kill’ and, it is to be hoped, some ‘cure’ too.

Posted 26 Feb 2015