Kathryn Janzen is an Associate Scientist and User Experience Coordinator at the Canadian Light Source. During her #LightSourceSelfie, Kathryn reflects on the light source community saying “The contacts between light sources are really important and everyone is very interested in sharing ideas. We’re also really interested in innovating and finding new ways to use the light source and finding new applications for old techniques.”
Göttingen researchers have developed nanobodies – a type of antibodies – that efficiently block the coronavirus SARS-CoV-2 and its new variants. Those nanobodies, which originate from alpacas inoculated with part of the SARS-CoV-2 virus spike protein – the receptor-binding domain that the virus deploys for invading host cells – could serve as a potent drug against COVID-19. The researchers used the X10SA crystallography beamline at the Swiss Light Source to characterize the interaction between the nanobodies and the coronavirus spikes at the molecular level.
Unlike antibodies, nanobodies can be produced on an industrial scale and at a low cost and therefore meet the global demand for COVID-19 therapeutics. The new nanobodies, which can bind and neutralize the virus up to 1000 times better than previously developed antibodies, are currently in preparation for clinical trials.
Read more on the PSI website
Image: The figure shows how two of the newly developed nanobodies (blue and magenta) bind to the receptor-binding domain (green) of the coronavirus spike protein (grey), thus preventing infection with SARS-CoV-2 and its variants.
Credit: Thomas Güttler / Max Planck Institute for Biophysical Chemistry
Many material properties are associated with structural disorder that exhibits local periodicity or correlations. A new form of this phenomenon exhibiting strong disorder-phonon coupling has been shown to arise in response to crystallographic conflict, with dramatic phonon lifetime suppression.
In recent years there has been a rapidly growing understanding that, hidden within the globally periodic structures of many crystals, various forms of disorder may exist that could form ‘locally periodic’ states, which the language of classic crystallography fails to describe. Such phenomena are commonly referred to as ‘correlated disorder’ and in many functional materials, from leading ferroelectric and thermoelectric candidates to photovoltaic perovskites and ionic conductors, this correlated deviation from perfect periodicity plays a pivotal role in governing functionality. As such, understanding the role of disorder, and the correlations that exist within it, is one of the defining challenges for the development of future functional materials.
Read more on the ESRF website
Image: Fig. 1: a) Reciprocal space reconstructions of the (hk2)s plane. All three samples investigated are shown with relevant at. % Mo indicated. Reflections are categorised and indexed in the bottom right quadrant, parent Bragg peaks (black) and diffuse superstructure reflections from two different domains (blue/green). b) Orientational relationship between parent (blue) and superstructure (red) unit cells for one of six possible domains. All atoms in the “shear plane” (highlighted red) move collinearly with the direction of motion indicated by arrows on the plane edge. Alternate planes, demarcated by I, I, III, … , move in antiphase. c) Top-down view showing the 45◦ relationship between the parent and superstructure. d) Schematic of the atomic motions in a “phonon plane.” Blue dashed and red dotted lines refer to interatomic bonding in the parent and superstructure unit cells, respectively.
Protein-structure studies at the Advanced Light Source (ALS) helped demonstrate that the primary target of antibody-based COVID-19 immunity is the part of the virus’s spike protein that can most easily mutate.
SIGNIFICANCE AND IMPACT
This work anticipated the rise of SARS-CoV-2 variants and guides the selection of antibody therapeutics that are likely to be more resistant to immune escape.
A better understanding of immunity
To better predict the course of the COVID-19 pandemic and to develop the best new therapeutics, researchers need to understand what regions of the SARS-CoV-2 virus are most critical to the immune response and how likely these regions are to mutate and evade immunity.
Two recent papers, relying in part on protein-structure studies at the ALS, have provided detailed information about the SARS-CoV-2 virus that causes COVID-19 and the human immune response to it. The results reveal where the virus surface protein is most likely to mutate, what the consequences of those mutations may be, and which types of antibodies may be the most effective therapeutics.
Read more on the ALS website
Image: Left: Composite model of the SARS-CoV-2 spike protein trimer with six mAbs shown bound to one RBD (Piccoli et al.). Right: The first RBD–ACE2 complex structure where the RBD is a variant, in this case N439K; the figure highlights a new interaction between the N439K residue and ACE2 (Thomson et al.).
Crystallography and cryo-electron microscopy are vital tools in the fight against COVID-19, allowing researchers to reveal the molecular structures and functions of the SARS-CoV-2 virus, paving the way for new drugs and vaccines. Since the start of the pandemic, the ESRF has mobilised its crystallography and cryo-electron microscopy expertise and made its new Extremely Brilliant Source available as part of the collective effort to address this critical global health challenge.
When the WHO declared the outbreak of COVID-19 a public health emergency of international concern in early 2020, it signalled the start of a race against time for scientists to understand how the newly identified SARS-CoV-2 virus functioned and to develop treatments for the disease. Structural biologists around the world pitched in, determining the structures of most of the 28 proteins encoded by the novel coronavirus. This remarkable collective effort resulted in over a thousand 3D structural models of SARS-CoV-1 and SARS-CoV-2 proteins deposited in the Protein Data Bank (PDB) public archive in just one year . Researchers and drug developers rely on these models to design antiviral drugs, therapies and vaccines. However, the speed and urgency with which the SARS-CoV-2 protein structures were solved means that errors could inevitably slip in, with potentially severe consequences for drug designers targeting certain parts of the virus’s structure.
Enter the Coronavirus Structural Task Force, an international team of 25 structural biologists offering their time and expertise to fix errors in structural models of the virus’s proteins in order to give drug designers the best possible templates to work from. Gianluca Santoni, crystallography data scientist in the ESRF’s structural biology group, is part of the task force, whose work is detailed in an article recently published in Nature Structural & Molecular Biology . “Every week, we check the PDB for any new protein structure related to SARS-CoV-2,” he explains. “We push structural biology tools and methods to the limit to get every last bit of information from the data, to evaluate the quality and improve the models where possible.”
To read more visit the ESRF website
Image: The coronavirus research project ‘COVNSP3’ is based on the use of the ESRF’s cryo-electron microscope facility, led by Eaazhisai Kandiah (pictured)
Credit: ESRF/S. Cande.
An international team of scientists, led by Kartik Ayyer from the Max Planck Institute for the Structure and Dynamics of Matter, Germany, has obtained some of the sharpest possible 3D images of gold nanoparticles, and the results lay the foundation for getting high resolution images of macromolecules. The study was carried out at European XFEL’s Single Particles, Clusters, and Biomolecules & Serial Femtosecond Crystallography (SPB/SFX) instrument and the results have been published in Optica.
Carbohydrates, lipids, proteins, and nucleic acids, all of which populate our cells and are vital for life, are macromolecules. A key to understanding how these macromolecules work lies in learning the details about their structure. The team used gold nanoparticles, which acted as a substitute for biomolecules, measured 10 million diffraction patterns and used them to generate 3D images with record-breaking resolution. Gold particles scatter much more X-rays than bio-samples and so make good test specimens. They are able to provide lot more data and this is good for fine-tuning methods that can then be used on biomolecules.
Read more on the European XFEL website
Image: Illustration of 3D diffraction pattern of octahedral nanoparticles obtained by combining many snapshots after structural selection.
Credit: Kartik Ayyer and Joerg Harms, Max Planck Institute for the Structure and Dynamics of Matter
Scientists have found that human T-cell lymphotropic virus, type 1 (HTLV-1) hijacks cellular machinery to establish an infection.
Research was undertaken using cutting-edge visualisation techniques such as X-ray crystallography, which was undertaken at Diamond, and single-particle cryo-electron microscopy (cryo-EM).
HTLV-1 is a virus that affects T cells, a type of white blood cell which plays a crucial role in our immune system. Currently, between five and 20 million people worldwide are infected by HTLV-1 and no cure or treatment is available. While most people infected with the virus do not experience symptoms, around two to five per cent will go on to develop adult T-cell leukaemia (ATL).
New research, led by a team from Imperial College London and the Francis Crick Institute, shows in atomic detail how HTLV-1 infects immune cells. By providing a more nuanced understanding of how the virus establishes infection in the body, the research will help to support the development of new, targeted therapies.
Read more on the Diamond Light Source website
Image: Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. Credit: NIAID
Research undertaken at Diamond has allowed scientists to create a super-enzyme that degrades plastic bottles six times faster than before.
The super-enzyme, derived from bacteria that lives on a diet of plastic, enables the full recycling of plastic bottles.
Plastic pollution is a global threat as plastics are rarely biodegradable and they can remain in the environment for centuries. One of the most abundant plastics that contributes hugely to this dire situation is poly(ethylene terephthalate) (PET).
PET is used largely in textiles, where it is commonly referred to as polyester, but it is also used as packaging for liquids and foodstuffs. PET’s excellent water-repellent properties led to it being the plastic of choice for soft drink bottles. However, the water resistance of PET means that they are highly resistant to natural biodegradation and can take hundreds of years to break down in the environment.
In 2018, researchers discovered that a unique bacterium (Ideonella sakaiensis 201-F6) was found feeding on waste from an industrial PET recycling facility. The bacterium had the amazing ability to degrade PET and use it to provide carbon for energy. Central to this ability was the production of a PET-digesting enzyme, known as PETase.
Read more on the Diamond website
In Feburary a new detector was installed at one of the three MX beamlines at HZB.
Compared to the old detector the new one is better, faster and more sensitive. It allows to acquire complete data sets of complex proteins within a very short time.
Proteins consist of thousands of building blocks that can form complex architectures with folded or entangled regions. However, their shape plays a decisive role in the function of the protein in the organism. Using macromolecular crystallography at BESSY II, it is possible to decipher the architecture of protein molecules. For this purpose, tiny protein crystals are irradiated with X-ray light from the synchrotron source BESSY II. From the obtained diffraction patterns, the morphology of the molecules can be calculated.
>Read more on the BESSY II at HZB website
Image: 60s on the new detector were sufficient to obtain the electron density of the PETase enzyme.
An HZB research team has developed a novel sample holder that considerably facilitates the preparation of protein crystals for structural analysis.
A short video by the team shows how proteins in solution can be crystallised directly onto the new sample holders themselves, then analysed using the MX beamlines at BESSY II. A patent has already been granted and a manufacturer found. Proteins are huge molecules that often have complex three-dimensional structure and morphology that can include side chains, folds, and twists. This three-dimensional shape is often the determining factor of their function in organisms. It is therefore important to understand the structure of proteins both for fundamental research in biology and for the development of new drugs. To accomplish this, proteins are first precipitated from solution as tiny crystals, then analysed using facilities such as the MX beamlines at BESSY II in order to generate a computer image of the macromolecular structure from the data.
Image: Up to three indivudal drops may be placed onto the sample holder.
A team of researchers from the University of Calgary has uncovered new information about a class of plant enzymes that could have implications for the pharmaceutical industry. In a paper published in the Journal of Biological Chemistry, the scientists explain how they revealed molecular details of an enzyme class that is central to the synthesis of many widely used pharmaceuticals, including the painkillers codeine and morphine.
The team used the Canadian Light Source at the University of Saskatchewan and the SLAC National Accelerator Laboratory to better understand how the enzyme behaves, which is crucial for unleashing its potential to make novel medicines. “Until this study, we didn’t know the key structural details of the enzyme. We learned from the structure of the enzyme bound to the product how the methylation reaction locks the product into a certain stereochemistry. It was completely unknown how the enzyme did that before we determined this structure,” corresponding author Dr. Kenneth Ng explained.
Stereochemistry is an important concept when it comes to safety and efficacy in drug design. A molecule can have a few different arrangements—similar to how your left hand is a mirror image of your right hand. These arrangements can lead to very different effects.
Image: group photo of some of the researchers involved with this project. From left to right: Ken Ng (Professor and corresponding author), Jeremy Morris (PhD graduate and second author), Dean Lang (PhD student and first author), and Peter Facchini (Professor, CSO of Willow Biosciences and senior author).
Malaria is endemic to large areas of Africa, Asia and South America and annually kills more than 400,000 people, a majority of whom are children under age 5, with hundreds of millions of new infections every year. Although artemisinin-based drug combinations are available to treat malaria, reports from Southeast Asia of treatment failures are raising concerns about drug resistance spreading to Africa. Fortunately, there is hope on the horizon because there are several new antimalarial drug candidates undergoing clinical testing as well as other promising drug targets that are under investigation.
An international research team has for the first time determined the atomic structure of a protein kinase called PKG in Plasmodium parasites that cause malaria—a finding that potentially will help create a new generation of anti-malarial drugs and advance fundamental research. PKG[i] plays essential roles in the developmental stages of the parasite’s complex life cycle, so understanding its structure is key to developing malaria-fighting therapies that specifically target PKG and not other human enzymes, according to researcher Dr. Charles Calmettes.
Image: PKG crystal.
Scientists analyze 3D model of proteins from disease-causing bacteria at the CLS.
Millions of people are affected by the Streptococcus pneumoniae bacterium, which can cause sinus infections, middle ear infections and more serious life-threatening diseases, like pneumonia, bacteremia, and meningitis. Up to forty percent of the population are carriers of this bacterium.
Researchers from the University of Victoria (UVic) used the Canadian Light Source (CLS) at the University of Saskatchewan to study proteins that the pathogen uses to break down sugar chains (glycans) present in human tissue during infections. These proteins are key tools the bacterium uses to cause disease.
They used the Canadian Macromolecular Crystallography Facility (CMCF) at the CLS to determine the three-dimensional structure of a specific protein, an enzyme, that the bacterium produces to figure out how it interacts with and breaks down glycans.
Image: The 3D structure of an enzyme from the disease-causing bacterium Streptococcus pneumoniae.
A team led by Berkeley Lab faculty biochemist Daniel Minor has discovered how a protein produced by bullfrogs binds to and inhibits the action of saxitoxin, the deadly neurotoxin made by cyanobacteria and dinoflagellates that causes paralytic shellfish poisoning.
The findings, published this week in Science Advances, could lead to the first-ever antidote for the compound, which blocks nerve signaling in animal muscles, causing death by asphyxiation when consumed in sufficient quantities.
“Saxitoxin is among the most lethal natural poisons and is the only marine toxin that has been declared a chemical weapon,” said Minor, who is also a professor at the UCSF Cardiovascular Research Institute. About one thousand times more potent than cyanide, saxitoxin accumulates in tissues and can therefore work its way up the food chain – from the shellfish that eat the microbes to fish, turtles, marine mammals, and us.
Image: A photo illustration showing the atomic structures of saxiphilin and saxitoxin, a red tide algal bloom, and an American bullfrog (R. catesbeiana).
Credit: Daniel L. Minor, Jr., and Deborah Stalford/Berkeley Lab.
As antibiotic resistance rises, the search for new antibiotic strategies has become imperative. In 2013, the Centers for Disease Control estimated that antibiotic resistant bacteria cause at least 2 million infections and 23,000 deaths a year in the U.S.; a recent report raised the likely mortality rate to 162,044.
New Cornell research on an enzyme in bacteria essential to making DNA offers a new pathway for targeting pathogens. In “Convergent Allostery in Ribonucleotide Reductase,” published June 14 in Nature Communications, researchers used the MacCHESS research stations at the Cornell High Energy Synchrotron Source (CHESS) to reveal an unexpected mechanism of activation and inactivation in the protein ribonucleotide reductase (RNR).
Understanding the “switch” that turns RNR off provides a possible means to shut off the reproduction of harmful bacteria.
RNRs take ribonucleotides, the building blocks of RNA, and convert them to deoxyribonucleotides, the building blocks of DNA. In all organisms, the regulation of RNRs involves complex mechanisms, and for good reason: These mechanisms prevent errors and dangerous mutations.
Image: William Thomas, a graduate student in the field of chemistry and chemical biology, collects data on ribonucleotide reductase.
Enzymes in the human gut can convert A blood type into O.
Half of all Canadians will either need blood or know someone who needs it in their lifetime. Researchers from the University of British Columbia have made a breakthrough in their technique for converting A and B type blood into universal O, the type that is most needed by blood services and hospitals because anyone can receive it.
In a paper published in Nature Microbiology, Stephen Withers and a multidisciplinary team of researchers from the University of British Columbia show how they successfully converted a whole unit of A type blood to O type using their system. They were able to remove the sugars from the surface of the red blood cells with help from a pair of enzymes that were isolated from the gut microbiome of an AB+ donor.
The Canadian Light Source (CLS) at the University of Saskatchewan (UofS) played a critical role in understanding the structure of a previously unknown enzyme that was part of this pair. The researchers were unable to identify what this unique enzyme looked like from the gene sequence they had. Crystallography, done at the CLS, was crucial for the researchers to understand how this enzyme works and why it had a particular affinity for the A type blood.