Oct. 31, 2018
The pungent bite of horseradish is familiar to most. Horseradish, along with its cousin wasabi, are used for their effects in condiments and dishes the world over - but horseradish has an important role that most people have never heard of. Enter horseradish peroxidase (HRP). HRP is a metalloenzyme (meaning it carries a metal atom to help it do chemistry) which uses hydrogen peroxide to induce a chemical change in a variety of substrates. This protein, found in high concentrations in horseradish roots, is vital to laboratory science - especially in the context of a test called ELISA. In this test, an antibody chemically linked to an HRP molecule is added to a solution, and allowed to bind to a protein-coated surface. A chemical marker is then added to the solution. This is where HRP comes in: if the antibody successfully bound to the surface, the attached HRP will begin to process the chemical marker, inducing a color change. After a certain amount of time, the reaction is stopped with a strong acid or base, and the color change is measured. More color change in the given timeframe corresponds to more HRP-antibodies bound to the surface. This, in turn, tells you how strong the interaction is between your antibody and the surface-bound protein! ELISA tests are used in labs that study proteins, but they are probably familiar to most people as the tests used to detect diseases like HIV in the bloodstream. Thanks to horseradish for doing its part to fight disease!
Oct. 22, 2018
Platypus milk may be exactly what we need to fight against antibiotic resistance. The platypus is one of few known monotreme species in the world. Monotremes are a small family of mammals that can lay eggs and produce milk for their young. Platypus milk is unusual since it's exposed directly onto the parent's belly, meeting the outside world before being delivered to the child. To prevent harmful effects from external bacteria, the milk contains antimicrobial proteins that kill or disarm these microorganisms. Shown here is one of these antimicrobial protein folds dubbed the "Shirley Temple," due to its ringlet structure (PDB: 4V00), by researchers at the Commonwealth Scientific and Industrial Research Organization (CSIRO). Finding ways to utilize the antimicrobial proteins in platypus milk may be the key to counteract continuously emerging antibiotic resistance in infectious agents.
Oct. 16, 2018
Dysregulation of glucocorticoid receptor (GR)-mediated signaling has been implicated in therapy resistance across a wide spectrum of cancer types. While the first GR antagonist mifepristone is being clinically evaluated, the search for more potent and selective small molecules continues. A recent publication presents a novel GR antagonist - ORIC-101- with better pharmaceutical properties, including reduced AR agonism. The graph presented at the attached link shows GR binding to ORIC-101 (PDB ID: 6dxk).
Oct. 8, 2018
Transcription factors are a class of proteins known for their role in controlling/regulating the rate of transcription of genes. Genetics aside; transcription is the process by which DNA is made into messenger RNA (mRNA-the molecule responsible for translation of proteins). Clearly, without transcription, no protein would be synthesized! Thus, transcription is a major component of what makes you and all living things tick. Additionally, controlling the rates at which transcription occurs is important. Which brings us to the specific transcription factor known as Nuclear factor 2 (NRF2) pictured here (PDB: 3WN7). NRF2 is responsible for the control of hundreds of genes that have a wide range of capabilities, including the activation of many anti-oxidant genes like glutathion S-transferase (GST), which is capable of deactivating pro-carcinogenic agents and transforming them into less reactive water-soluble conjugates. You read that right; it helps you flush pro-carcinogens from your body! To learn more about interesting molecules and about our molecular modeling capabilities follow us on Instagram.
Oct. 1, 2018
Many of the foods we eat contain a large number of polysaccharides. These molecules go through many metabolic processes within us to produce glucose. The glucose is then transported from the extracellular space into cells where it is used to generate ATP- which is the energy that our bodies use to carry out work. The real trick here is getting glucose through the cell membrane. Two important molecules play a role in this process. The first is insulin which is released from pancreatic Beta cells when there is an increase in glucose concentration. The second is the insulin target receptor (pdb:4ZXB) and this week’s featured molecule; Insulin Receptor (IR). IR is a subtype receptor of the tyrosine kinase family, which is also activated by IGF-1 and IGF-2. Once insulin binds to IR a cascade of events occurs via the PI-3K signaling pathway which causes the insertion of GLUT-4. GLUT-4 is the glucose transporter that walks glucose across the cell membrane. As you can see, insulin receptor is very important and errors in the receptor or the signaling pathway can be fatal if not treated promptly. A common pathology that causes problems with this pathway is diabetes mellitus type 2. In this form of diabetes there is an insulin resistance to some of the IR in the body. Patients with type 2 diabetes suffer from an elevated plasma glucose level which may lead to glycosuria and ketoacidosis. Treatment for type 2 diabetes involves an individual making lifestyle changes, self-monitoring blood glucose levels, and taking certain medications.
Sept. 24, 2018
We first discussed the Ebola Virus on our Instagram back in 2016 ( http://ow.ly/yxpC30lWRPM ). At the time, the disease was making headlines due to an outbreak that began in 2014 which was the deadliest in history. There are still no antiviral drugs nor vaccines that have been approved for Ebola, but there is a treatment that entered phase I clinical trials as of March of this year (2018). The treatment is a monoclonal antibody (mAb) – an antibody that has been cloned from a unique parent cell – known as mAb114. It was isolated from a human survivor of the 1995 Ebola outbreak in Kikwit, Democratic Republic of the Congo. Thus far, the antibody has been shown to protect primates from a lethal injection of Ebola days after infection. The phase I trial is investigating whether varying doses of the treatment are safe for humans. As we mentioned in our previous post, the Ebola Glycoprotein (picture here, PDB: 5JQ3) was an excellent candidate to design a treatment and this is the very protein to which mAb114 binds.
Sept. 17, 2018
Plants contain cells with walls constructed from a molecule called cellulose. Cellulose is an insoluble dietary fiber for us humans which is why we don't make dinner salads out of just any leaves and grass - we can't derive any nutrients from it! It takes a specialized organ that only ruminants have to digest the molecule. The organ, which the phylogenetic suborder derives its name, is called a rumen. The rumen is host to a diverse microbiome which ferments the plant matter to extract nutrients from cellulose. The bacteria in this microbiome use the pictured dockerin (RSCB 5LXV) to degrade carbohydrates and share the results with their host.
Sept. 10, 2018
Rheumatoid-arthritis (RA) is an autoimmune disease where your body attacks your connective tissues, primarily the joints, heart, and lungs. The way this disease works is much like other autoimmune diseases; the body releases antibodies which bind to native tissues. Once attached, the antibodies signal to your immune cells to ATTACK! This releases histamine and other cell-killing chemicals which cause the connective tissue to become inflamed and damaged. The release of histamine is a positive feedback loop, so more histamine is released to the area. Thus the pain of RA can become progressively worse once symptoms arise. Patients often report having good days and bad days, depending on a variety of factors such as stress, smoking, and level of physical activity. Over time, the damage can cause joints to become stiff and unstable. It is unknown how and why RA starts, but it is linked to genetics. Fortunately, treatment for RA is fairly effective and can dramatically increase quality of life. Pictured is the protein 1ADQ which is a characteristic antibody of RA.
Sept. 4, 2018
Many of our interactions and observations in our everyday life are made possible due to the complicated system that allows us to hear. One of the unsung heroes of the inner ear is Cadherin-23. Many of us are familiar with the sensitive "hairs" in our cochlea that respond to the vibrations caused by auditory stimulation. These "hairs" are actually stereocillia (upper left) that are long, thin projections from cells that line the inside of the inner ear. As sound waves pass through these stereocilia, they bend, causing the distance between the tips to increase. Cadherin-23 serves to link these tips together, and pulling on it activates a protein called an ion channel. This, in turn, fires up the nerve underneath the hair cell and sends a message to the brain that sound waves are traveling through the ear. Feel free to let us know what you use Cadherin-23 for in a comment below!
Aug. 27, 2018
Programmed cell death protein 1 (PD-1) is found on the surface of cells and plays a role in regulating against autoimmunity by preventing the immune system from attacking our body's own healthy tissues. Programmed death-ligand 1 is a protein (also found on cell membranes) that binds to PD-1 to send a signal promoting apoptosis (cell death) in antigen-specific T-cells. This mechanism blocks these specific T-cells from reaching their target, such as healthy cells, and therefore prevents autoimmune diseases. Unfortunately, PD-L1 has been found on the surface of cancer cells. The T-cells are unable to attack the cancer, allowing the disease to proliferate. Cancer immunotherapy takes advantage of this type of knowledge to create antibodies that can bind to certain proteins and guide the immune system toward eliminating cancer cells. Shown is an example of this (PDB 5ggs) where Prembrolizumab, an antibody drug approved by the FDA, binds to PD-1 and functionally prevents cancer cells from "hiding" from our immune system. At @macromoltek , we use our in-house antibody modeling and design software to aid in the development of life-changing antibodies just like these.