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New structure of key protein holds clues for better drug design

The scientists working at the Scripps Research Institute (TSRI) have elucidated the molecular structure of  a key protein, which is used extensively in drug design. With this discovery, scientists can now develop to new ways to combat infectious diseases. They have discovered the structure of the protein named A2A adenosine receptor (A2aAR), which is a member of the G-protein-coupled receptor (GPCR) family. Approximately 40 percent of all approved pharmaceutical drugs use this protein as target molecule.

Furthermore, scientists have uncovered the detailed signaling mechanism of the protein A2aAR, helping us understand the inner workings of this proteins. For example, an amino acid of A2aAR acts like a “toggle switch” and controls the signaling processes of the cell membrane. Journal Cell published this path-breaking discovery today. Based on imaging techniques, it can be inferred that shape of proteins changes.

The protein A2aAR and other molecules of the GPCR family are embedded into plasma membrane of human cells. A normal human body contains more than 800 GPCRs and each protein molecule regulates the metabolic functions of the human body. Scientists have reported that the protein A2aAR is associated with the regulation of blood flow and inflammation. The harmful effects of caffeine are also alleviated by the protein A2aAR. For treating Parkinson’s disease, A2aAR is a relatively new target. Moreover, the protein A2aAR is reported to be a relatively new target in the treatment of cancer.

In recent years, X-ray crystallography has been used to determine the three-dimensional structure of A2aAR protein in previous studies. The X-ray images show that A2aAR protein resembles a chain, and it crisscrosses the cell membrane. An opening is present on the side that faces out of the cell. For signaling associate proteins inside the cell, a section of the GPCR structure emerges out of the membrane and gets associated with drugs.

During inactive and active-like states, an outline of the receptor’s shape was provided by the crystal structure. When A2aAR was combined with new candidate compounds of the pharmaceutical industry, they acted as binding partners; however, no motion and changes in cell structure was observed.

In this study, researchers realized that they need to establish the molecular mechanism through which A2aAR works in combating diseases. Nuclear magnetic resonance (NMR) spectroscopy was used by researchers for investigation. In this process, strong magnetic fields were used to probe the samples.

By using NMR technique, the structure of proteins was determined by scientists. Scientists also investigated the dynamic properties of the solutions at temperatures prevalent in the human body. The team of researchers visualized the internal structural changes in the A2aAR proteins.

In this study, researchers investigated the effects of binding drugs with extracellular surface. Changes were observed in the structure of proteins and in the dynamics of the protein surface at an intracellular level. Thus, scientists discovered the mechanism of signal transfer through intracellular pathways. Chemists modified drugs and manipulated the switch to control A2aAR signals.

 

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Innovative colitis treatment through precision editing of gut bacteria

Medical researchers at Southwestern Medical Center, Utah, performed precision editing on the bacterial colonies found in the gastrointestinal tract. This reduced the inflammation’s severity and colitis caused in experimental mice.

The primary strategy was to target cellular pathways associated with metabolic activities, which are associated with gastrointestinal inflammation. The main object was to prevent or reduce the inflammation caused in mice with colitis. At the same time, the control animals showed no signs of inflammation; the bacterial colonies in the gut were balanced and healthy.

This path-breaking discovery was published in latest issue of Nature magazine. A framework was developed from our results, and the bacterial species that line the gastrointestinal tract were precisely altered to reduce the inflammation caused by colitis and other forms of inflammatory bowel disease [IBD].

In this experimental study, we used a heavy metal called tungsten, which is dangerous when ingested in high doses. It should be noted that no heavy metal is safe for consumption. Our primary goal was to develop a novel therapy that induces a similar effect but within the acceptable limits of safety.

There is a diverse population of microbes, which form a thin line on the gastrointestinal tract. These microbes are essential for the maintenance of good health. They help in digestion, improve the immune system, and effectively combat all kinds of infections.

When there is an imbalance in microbial populations, these beneficial bacteria become a nuisance as they develop invasive qualities and drive out species that compete with them for space. It is difficult to understand the biology of gut microbiota because they are  highly diverse in nature.

In humans, several bacterial species are found in the gastrointestinal tract. The composition of species differs extensively for individuals. The composition of gut microbiota changes considerably, causing many chronically progressive diseases, such IBD, ulcerative colitis, and Crohn’s disease.

According to Centers for Disease Control and Prevention, at least 1 million adults are affected by IBD in the United States of America . Currently, there is no cure for such diseases. The gut microbiota also undergoes changes in patients with Type 2 diabetes, HIV-related intestinal disease, colon cancer, and necrotizing enterocolitis. These diseases are also observed in certain premature infants.

The bacteria found in the microbiota of the gastrointestinal tract belonged to enterobacteriaceae family, causing many inflammatory diseases.  In healthy gut, a small number of healthy bacteria are present. They belong to E.coli (Escherichia coli). These bacteria also protect pathogenic bacteria, such as Salmonella, which is responsible for food poisoning in humans. In mouse afflicted with colitis, there is an uncontrolled growth of enterobacteriaceae species.

In a paper published by Cell Host & Microbe, it was reported that cellular energy was produced by Enterobacteriaceae family. Gut bacteria uses this energy for improving growth and obtaining nutrients. Unique metabolic pathways were used to improve the growth and drive out beneficial bacteria at the time of illness.

These unique pathways are used to improve inflammation in gut. In current study, tungsten was used to inhibit the pathways obstructing metabolism. An inflammation develops due to incessant growth of pathogenic bacteria.

These researchers have reported that bacteria absorbed tungsten, and they developed an important cofactor of bacteria. Due to the inflammation, enterobacteriaceae lost its capacity to generate energy.

A soluble salt of tungsten was orally administered to patients. The useful bacteria were not affected in this innovative experiment. This is because a particular the cofactor could not govern the metabolism of beneficial bacteria.

The proliferation of enterobacteriaceae was stopped in our current experiment. When enterobacteriaceae  species were present in correct ratios, colonization would be resisted by bacterial pathogens.

By controlling the proliferation of bacteria, inflammatory episodes were prevented completely. With miniscule experimental evidence, it can be postulated that diseases of the gut worsen due to changes in the composition of microbiota.

In this study, it was found that the inflammation of the gut was reduced and a normal state was achieved by using tungsten treatment. In most experiments, tungsten was used to rectify a molecular target. This treatment was therapeutic for patients. At the same time, tungsten is the heavy metal that provokes neurological and reproductive diseases.

Conventional approaches are focused on treating bacterial pathogens. However, this path-breaking research is quite useful to harness bacteria in the normal gut. The composition and the function of gut microbiota was controlled.

Most doctors prescribe broad spectrum antibiotics. The final objective is to tarnish numerous bacteria in the gut. Whenever a patient visits the clinic in a critical state, most doctors prescribe antibiotics and do not conduct tests to identify the specific pathogens in the human body. In such a scenario,  the prescribed antibiotics have broad-spectrum activity, killing most pathogens and beneficial bacteria.

Only one family of bacteria, enterobacteriaceae, was targeted in our study. Although results are promising, more studies must be conducted to identify potential therapies that cause human diseases.