Illuminating Biological Structures at the Atomic and Molecular Levels
This study highlights the importance of being aware of, and perhaps monitoring, the non-human animal populations that humans frequently contact. Because the COVID-19 virus can infect a wide-range of animals, non-human animals can host mutations that lead to variants of concern in humans.
This research uncovers a mechanism by which EBV infection and MS disease are connected. The authors have found that antibodies that target the virus can also target cellular proteins in the central nervous system. By studying this system, scientists will gain a better understanding of the origins of autoimmune disease. This research may also aid the development of potential therapies for these diseases.
This study provides high resolution crystal structures of proteins important for skeletal and heart muscle cell function. Having these structures allows an understanding of why certain genetic mutations affect the function of heart cells leading to cardiomyopathy disease.
The deep understanding of Lsd14 structure and function found through this research will help elucidate the architectures and mechanisms of other polyketide synthases. These first high resolution structures will aid in the development of engineered enzymes that synthesize molecules important to the medical and health fields.
RNA biologists at the University of Rochester Medical Center (URMC) have discovered that RNA, the chemical cousin of DNA, can bind two metabolites (small molecules) at the same time in a single binding pocket, causing those molecules to interact. This discovery, published in Nature Communications, could lead to new antibacterial drugs while helping to fill a gap in the controversial “RNA world” theory, which suggests that RNA molecules enabled life to evolve on Earth 3.5 billion years ago.
In this study, the researchers have found the current models of general enzymatic function to be lacking, replacing the structure-function paradigm with an “ensemble-function” paradigm. This takes into account the reality for structural movement in enzymes and also suggests that this conformational flexibility is necessary for proper enzyme function.
This research furthers our understanding of cytokine-receptor binding and shows a path to modify immune system action by engineering cytokine structure. This could be useful for diseases like cancer, where activation of T cells without activating NK cells would be advantageous.
This research demonstrates that the recently developed SAXS-TT technique is able to characterize myelin quantity and structure in mouse and human brains. This technique provides an important tool to assess myelin health in an accurate and non-destructive way, with results as accurate as or more accurate than the currently used methods.
This study sheds light on an unusual mechanism from an unusual enzyme that performs an unusual, but important, reaction. The results of this study suggest that the previously favored theories for MCR mechanism are not correct. The long-range electron transfer mechanism proposed by the researchers opens a door to new possibilities to understand how these methanogens are able to synthesize and break down methane.
This research provides evidence that nanobodies may be an effective COVID-19 treatment that is less costly and more robust than monoclonal antibody treatment. Through understanding exactly how different nanobodies interact with the viral spike protein, the researchers were able to design nanobodies that were much more effective.
This research introduces a twist to our understanding of this basic process of reducing nitrogen gas into a form available for biochemistry. Not only is this enzymatic process basic and essential for all life, but it could be used for bio-technologies, including fuels and fertilizers.
Through studying functional, crystallized enzymes, scientists were able to piece together the reaction mechanism for the important, but not well understood, enzyme HAO. Their work revealed an unknown activity that helps to explain the biological behavior of the products of the reaction. This study will greatly inform research that seeks to target the HAO enzyme for therapeutic purposes.
The detailed atomic-scale structure of the antibody interactions with the virus should help accelerate vaccine design. Moreover, the identification of IGHV3-53-encoded antibodies as key elements of the immune response to COVID-19 suggests that levels of these antibodies might be useful as an indirect marker of success in ongoing and future vaccine trials.
The textbook explanation of the Minamata tragedy that inorganic mercury pollution was bio-transformed in the environment to methylmercury may not be correct. It appears the factory effluent contained organic mercury compounds now deserves to be reevaluated. Much of what we know about the effects of human exposure to methylmercury derives from the Minamata poisoning, so what we thought we knew may now need to be reevaluated
This study bridges the gap between research on functional bacterial amyloid proteins and the better-studied pathological amyloid proteins. Researchers will continue to investigate bacterial amyloids to better understand the formation of bacterial biofilms. These results will ultimately help to develop strategies to disrupt disease causing biofilm formation.
By using knowledge of inorganic chemistry, these scientists were able to engineer proteins that assemble into complex polymers in predictable ways. One of their variants showed flexibility to form different symmetries depending on the environment. This study advances the field of protein engineering by inventing ways to engineer protein cage architectures and assemblies.
Because the scientists carefully changed the electron distribution but not the atomic positions in the chromophore, they revealed the important role electrostatics plays in photoisomerization. This discovery enriches our understanding of light-sensitivity in biological systems and will help scientists engineer light-sensitive artificial systems.
Nerve, muscle, and heart cells are activated by the influx of sodium ions into the cells causing an increase in positive charge inside cells. In a carefully regulated system, sodium passes across cell membranes via a variety of sodium ion channels, which open during activation and close when not active. Nav1.7 is a type of sodium channel that has an important role in pain sensation.
The structure of VISTA found through this work will help researchers develop treatments for a variety of cancers. This structure has already led to an understanding of the interaction of VISTA with a clinically relevant anti-VISTA antibody and the natural binding partner on interacting immune cells.
The researchers used the APS and SSRL Beam line 9-2 to collect macromolecular crystallography data. They additionally used SSRL Beam Line 4-2 for small-angle x-ray scattering (SAXS) experiments. The resulting structure of the entire toxin TcdB was resolved to almost atomic resolution.
This work identifies a small molecule that could be effective in humans against many forms of influenza A virus, paving the way for design of broader-acting therapeutics. Such small molecules could be an alternative to the yearly reformulations of the seasonal vaccine.
This breakthrough research demonstrates that unnatural, synthetic bases can be incorporated into DNA helices to fill the same structural and functional roles as natural DNA. This is evidence that A, C, G, and T are not exclusively special. Therefore, if extraterrestrial life has DNA, it could plausibly use different bases than terrestrial life.
The researchers used SSRL Beam Lines 12-2 and 14-1 to determine the crystal structures of several NT5C2 mutations. From the 15 structures analyzed, along with modeling, genetic, and functional analyses, they deciphered three different mechanistic classes for these mutations.
The researchers used SSRL Beam Line 12-2 to determine crystal structures of a functional α1GABAAR variant bound and unbound to alphaxalone. Their structures revealed the binding site of alphaxalone at the base of the TMD and suggest a mechanism for the drug’s action. Through this allosteric binding site, alphaxalone triggers the activation and subsequent desensitization of the channel by inducing far reaching conformational changes.
Mammalian hosts defend against invading pathogens via the import of toxic concentrations of copper into the phagolysosome. To combat this host-defense strategy, gram negative pathogens respond via sophisticated copper export systems which are able to neutralize the copper onslaught.
The immune system is formed by a complex network of cells that have the ability to kill pathogens (such as viruses and bacteria) while at the same time do not cause autoimmunity or allergy, which could harm the host.
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that are integral to diverse physiological processes in animals, including tissue regeneration, cardiac function, brain development, and the progression of cancer.
Natural and engineered nanomaterials are particles with one dimension <100nm. They can have unique reactivity compared to larger particles with the same chemical composition. However, there is still limited understanding of how these nanophases will behave once released into complex natural ecosystems.
Influenza also called “Flu” is a disease of the human respiratory tract caused by influenza virus. Each year, seasonal influenza can cause severe and widespread disease in the human population and cost billions of dollars to the world economy.
To understand NAM, one needs to look at one of the basic components in skeletal muscle. Just prior to the muscle contraction, an electrical signal is generated in the plasma membrane, causing it to depolarize.
Chromatin is the complex of DNA and proteins that comprises the physiological form of the genome. Non-covalent interactions between DNA and histone proteins are necessary to compact large eukaryotic genomes into relatively small cell nuclei.
All living things require energy and an organism's ability to extract energy from its surroundings is a key requirement of survival. Until recently it was thought that there were only two methods to generate and conserve the energy required for cellular metabolism and survival.
Iron-sulfur (Fe-S) clusters are small, inorganic cofactors that are essential for all living organisms by participating in a variety of functions such as substrate activation, DNA replication and repair, and respiration.
CRISPR (Clustered regularly-interspaced short palindromic repeats) immune systems provide prokaryotes with adaptive immunity against phage and other foreign genetic elements.
Bacterial microcompartments (BMCs) are large, specialized subcellular compartments for colocalizing enzymes to enhance reaction rates, protect sensitive proteins, and sequester toxic intermediates.
A research team based at The Rockefeller University has identified a potent new weapon against the Zika virus in the blood of people who have been infected by it.
The ends of our chromosomes are protected by nucleoprotein complexes known as telomeres. The hetero-hexameric shelterin complex (POT1, TPP1, TRF1, TRF2, TIN2 RAP1) binds single and double-stranded telomeric DNA and plays a critical role in telomere length regulation and maintenance.
Intracerebral hemorrhage (ICH) is a subtype of stroke characterized by bleeding within the brain. Rehabilitative therapy is key to alleviating the functional deficits suffered by ICH patients. A more thorough mechanistic understanding of ICH pathophysiology and rehabilitation-induced recovery will likely lead to improvements in existing therapies and the development of novel treatments.
Microtubules (MTs) are hollow, nanometer-scale cylinders comprised of globular dimeric tubulin subunits that are involved in a variety of cellular functions, including intracellular trafficking and cell division. Tubulin subunits align end-to-end to form linear protofilaments that interact laterally in stabilizing the tubular wall.
Axl is a receptor that belongs to the TAM family of receptor tyrosine kinases, which also includes Tyro3 and Mer. Axl has recently been shown to be an important oncology target, as signaling through the receptor drives metastasis, confers therapeutic resistance, and promotes disease progression across a myriad of human malignancies.
RNAs play many functional roles in biology, from non-coding RNAs directly regulating gene expressions to structured RNAs acting as molecular machines essential to chromosome maintenance, alternative pre-mRNA splicing, protein synthesis, and protein export. RNA function typically involves a series of conformational steps, which can be considered as different conformational states that can be adopted by the same RNA.
The nuclear pore complex (NPC), a very large macromolecular machine embedded in the nuclear envelope, is the sole gateway for the bi-directional transport of macromolecules between the nucleus and cytoplasm. The NPC is also involved in diverse cellular processes, including transcription, mRNA maturation, and genome organization.
Pili (or fimbriae) are hair-like structures on the cell surface of many bacteria. Pili can play a variety of functions in bacteria, such as conjugation, mobility and adhesion, and often serve as primary virulence factors. Pili are formed by noncovalent or covalent oligomerization of component proteins, pilins or fimbrilins.
Copper serves as a redox center in metalloproteins, often cycling between the +1 and +2 oxidation states. Oxidases, such as petidylglycine monooxygenase (PHM), bind oxygen at Cu(I) sites giving rise to "oxo" reactive intermediates capable of oxidizing organic substrates.
Using macromolecular crystallography beam lines at SSRL and the ALS scientists Alexander F. Kintzer and Robert M. Stroud at the University of California, San Francisco (UCSF) determined the structure of the first intracellular, voltage-gated, transmembrane protein ion channel, called two-pore channel 1 or TPC1, with an allosteric inhibitor Ned-19 bound to the outside of the channel.
Genes encoding members of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway are frequently mutated in human cancer. RAS (a small GTPase) and RAF (a serine/Threonine kinase) are two major nodes on this important signaling axis. Constitutive activation of BRAF, a member of the RAF family, has been shown to promote RAS independent MAPK pathway up-regulation1.
“CLC” transporters are secondary active-transport membrane proteins that catalyze the transmembrane exchange of chloride (Cl-) for protons (H+). This exchange plays an essential role in proper cardiovascular, neuronal, muscular and epithelial functions. Several diseases arise from CLC defects, and several CLCs are therapeutic targets.
Translocator protein (TSPO) is an ancient conserved protein whose functions in bacteria and higher eukaryotes are yet to be clearly defined in spite of more than 30 years of study. In mitochondria, it was first recognized as an outer membrane protein that binds benzodiazepine drugs, but distinct from the central nervous system site, the GABAA receptor.
Scientists at Stanford University School of Medicine have determined the 3-D structure of a complex of synaptic proteins that controls the release of signaling chemicals (called neurotransmitters, such as glutamate, dopamine or serotonin) from brain cells in less than one-thousandth of a second, which ultimately could help unlock a new realm of drug research targeting brain disorders.
C-H bond activation is often considered the “holy grail” of inorganic chemists, as the ability to specifically activate C-H bonds would be one of the most used transformations in all of chemistry. Cytochrome P450s (P450s) are thiolate ligated heme proteins that are often referred to as nature’s detoxifiers and can do this difficult C-H bond activation with ease. P450s are known to hydroxylate C-H bonds on the order of about 98-100 kcal/mol.
Resveratrol is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects by initiating a protective stress response. Resveratrol is produced in grapes, cacao beans (dark chocolates), peanuts (peanut butter), Japanese knotweed, blueberries and some other plants, in response to environmental stress conditions including infection, drought and ultraviolet radiation.
A major goal in molecular design and engineering is the creation of new enzymes from scratch. However, the design of 3-dimensional protein architectures from first principles represents a formidable challenge, and as a result, the generation of new enzymatic activities has primarily relied on repurposing the interiors of pre-existing protein folds such as TIM barrels and αβ-hydrolases.
All living organisms depend on the availability of nitrogen for incorporation into the basic biological building blocks such as amino acids and DNA. Globally the largest reservoir for nitrogen is the atmosphere, with an N2 content of roughly 78%. However, as a highly unreactive gas, most organisms are unable to directly utilize dinitrogen due to the severe energy barrier required to break the N-N-triple bond.
Viruses that infect bacteria and archaea are the most abundant biological entities on the planet1. To defend themselves against these pervasive viral predators, bacteria have evolved sophisticated adaptive immune systems that rely on a repetitive chromosomal locus called CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat). Each CRISPR locus consists of short (30-40nt) repeats that are separated by viral or plasmid derived spacer sequences of about the same length.
Immune pathways protect all organisms from infection by genetic invaders such as viruses. It was recently discovered that prokaryotes protect against invasion by bacteriophages via an RNA based adaptive immune system, called the CRISPR system. By acting as a barrier to the exchange of genetic information, a major route for the acquisition of antibiotic-resistance and virulence factors, the CRISPR system modulates the evolution of pathogenic bacteria.
There has been a long-standing interest in blocking agents against influenza entry, such as inhibitors that can target the receptor binding site on the hemagglutinin surface glycoprotein (HA) to prevent viral attachment to host cells. Molecules have been designed based on the sialic acid receptor, although with very little success since sialic acid only has millimolar affinity to the HA.
Copper is an essential nutrient for most organisms. However, it is toxic at high concentrations and, in fact, is used by macrophages to kill invading microbes. To counter the lethal effects of both environmental and host-defense onslaught, bacteria have devolved intricate efflux systems that impart full copper resistance.
Redox-inactive metal ions play crucial roles in tuning the reactivity of oxygen-containing metal complexes and metalloenzymes such as the oxygen-evolving complex (OEC) in photosystem II (PSII) and its small-molecule mimics.
The human immune system relies on a network of protein sensors poised to detect foreign bacteria and viral pathogens. Researchers have discovered several families of receptors to explain how cells detect different types of microorganisms, but the evolutionary origin and specific signaling mechanism of these receptors often remain unclear.
Secondary metabolites produced by microorganisms have a market value of over $30 billion annually, and nearly half of these compounds are naturally produced by bacteria in the phylum Actinobacteria. Phylum is a taxonomic rank in biology. It is below kingdom (e.g. Animal, Plant, Fungi etc.) and above class (e.g. Mammalia). Although there are over a dozen classes of secondary metabolites, the polyketides are arguably the most versatile with medically relevant activities including antibiotic, anticancer, immunosuppressive, anti-parasitic, and cholesterol-lowering properties.
Cytochrome P450s (P450s) are a family of monooxygenase enzymes that are nearly ubiquitous in nature. P450s are often described as biological blowtorches due to their incredible oxidizing power: They can hydroxylate C-H bonds of about 98-100 kcal/mol. P450s are responsible for the phase I metabolism of 75% of all pharmaceuticals in vivo and are thusly referred to as nature’s detoxifier.
T cells are tasked with detecting and counteracting infection and cellular dysfunction within an organism. Each T cell expresses a unique T-cell receptor (TCR), which is selected during T-cell development to bind to major histocompatibility complexes (MHCs) that display short (~8-15 amino acid) linear peptide antigens.
The Escherichia coli (E. coli) proteome consists of 5993 proteins, of which 853 are involved in primary metabolic processes critical for the survival and functioning of the cell1. Fatty acid biosynthesis is at the core of primary metabolism responsible for the synthesis of fatty acids, essential metabolites that are the major components of cellular membranes and energy storage.
As x-ray crystallographers, we often assume that when we build a model into an electron density map, that we can assign the known biological functions of the protein to the structure we see in the map. But what if the protein can make more than one equally valid structure?
For approximately 2,000 years, the Chinese have been using the Chang Shan herb to treat malaria-induced fevers. A derivative of the herb's active ingredient has also been utilized in clinical trials for cancer and other therapies. Previous studies showed that the derivative, called halofuginone (HF), binds to an enzyme known as prolyl-tRNA synthetase (ProRS). Inhibition of ProRS by HF requires the additional presence of adenosine triphosphate (ATP), interestingly one of ProRS's three native substrates. Recent studies have shed new light on the structural interplay of ProRS, HF and ATP.
Argonaute proteins play an important role in the biological process of RNA interference (RNAi). Scientists have now determined the crystal structure of human Argonaute2, thereby making progress toward a detailed understanding of Ago2 interactions with target RNA which may benefit the design of novel RNAi therapeutics.
During evolution, organisms added new domains to tRNA synthetases, which are believed to enable additional functions beyond protein synthesis. For the very first time researchers have established an essential role for an appended domain of tRNA synthetase in organisms.
UCE plays a key role in the functioning of lysosomes, cellular sacs full of digestive enzymes that break down bacteria, viruses and worn-out cell parts for recycling. When this recycling process goes awry, it can cause rare metabolic diseases such as Tay-Sachs and Gaucher, which often cause death in affected children by their early teens. Three years ago, researchers discovered that three mutations in UCE itself were linked to persistent stuttering that is passed down in families.
Cells bind each other using specialized cell surface adhesion complexes called adherens junctions. These complexes direct the formation of tight, Velcro-like contacts that are essential for the development, architecture, maintenance, and function of tissues in all higher organisms. Exactly how this cell to cell binding is accomplished has not been fully understood. Researchers from the Florida campus of The Scripps Research Institute (TSRI) have now solved a piece of this puzzle by determining the structure of α-catenin using SSRL's Beam Line 11-1.
Aminoacyl-tRNA synthetases are required in all three domains of life to add the correct amino acid to its cognate tRNA, an essential step in protein synthesis. Despite their importance, no structure had been reported for any full-length eukaryotic, glutaminyl-tRNA synthetase (GlnRS), although structural data for two prokaryotic GlnRS species exists.
Cys-loop receptors in eukaryotic cells control fast synaptic transmission and are important targets for various therapeutics which include general anesthetics. Although technical challenges have limited the determination of high-resolution structures for Cys-loop receptors, researchers from the University of Pittsburgh School of Medicine have taken advantage of two homologous proteins: the pentameric ligand-gated ion channels (pLGICs) found in the bacterium Erwinia chrysanthemi (ELIC) and the cyanobacterium Gloebacter violaceus (GLIC). The researchers carried out crystallographic studies of these pLGICs on SSRL Beam Line 12-2, investigating the structural underpinnings of the pLGIC activation process and the structural basis of anesthetic modulation of pLGICs.
Recently, scientists at the University of California, Berkeley and Lawrence Berkeley National Laboratory and their collaborators synthesized a series of metal-organic frameworks (MOFs) with pores up to 98 Å in diameter—large enough to house protein molecules. For the first time the researchers were able to design strategies to overcome three major obstacles to increasing pore capacity...
Lassa virus is endemic in Western Africa, and is the most common cause of viral hemorrhagic fever, infecting an estimated 300,000-500,000 people annually. It is also the hemorrhagic fever most frequently transported out of Africa to the United States and Europe. Understanding the key proteins of Lassa virus and any Achilles' Heels written into their protein structures will enable development of therapeutics for medical defense. Recent analysis of the crystal structure of the virus' RNA binding domain done at SSRL may have revealed one promising area of vulnerability.
Of the 11 species of Neisseria bacteria that colonize humans, 9 of them coexist peacefully with us. However, two can cause serious diseases N. gonorrhoeae, responsible for the sexually transmitted disease gonorrhea, and N. meningitidis, which causes septicemia and meningitis. Commercially available vaccines exist for four of the five known disease-causing serogroups of N. meningitidis (A, B, C, Y, W135) but no vaccine exists to combat serogroup B (menB); nor is there a vaccine available against N. gonorrhoeae. One target for vaccine development against menB and N. gonorrhoeae is the iron transporters found on the pathogens' surfaces. Cut off their access to iron and these pathogens cannot survive.
Until now this has been achieved only when extensive knowledge of the mechanism of the reaction is available. Recently, however, researchers have used a clever in vitro strategy to synthesize an artificial RNA ligase enzyme capable of a previously unknown catalytic activity, and to do so they began with a protein not associated with catalysis. A team of scientists led by Burckhard Seelig of the University of Minnesota have now determined the unique structure of this novel biocatalyst using NMR and synchrotron-based Zn K-edge EXAFS at SSRL's Beam Line 9-3
Brain injuries from stroke are both common and costly. The NIH has estimated that the total annual cost of stroke in the United States is $43 billion including direct medical care and the costs related to lost productivity. It has been recognized that rapid diagnosis and treatment is essential to limit neuronal cell death from either a bleed into the brain (hemorrhagic stroke) or a blockage that deprives part of the brain of oxygen (ischemic stroke). The Synchrotron Medical Imaging Team, a group of Canadian, US, and European scientists from diverse backgrounds are collaborating to better understand the underlying chemistry of stroke and how to best image and treat stroke patients.