Genes control the most basic functions of the cell, including what proteins to make and when. In 2003, the Human Genome Project created a draft map of our genes, and now researchers have completed a draft map of the human proteome—the set of all our proteins. The map, which includes proteins encoded by more than 17,000 genes as well as ones from regions of the genome previously thought to be non-coding, will help advance a broad range of research into human health and disease.
Category: Molecular Structures
Roughly half the world’s population is now at risk for mosquito-borne diseases other than malaria, such as yellow fever, West Nile virus and dengue fever. These three diseases are caused by flaviviruses, a type of virus that carries its genetic material as a single strand of RNA.
Flaviviruses have found a way not only to thwart our bodies’ normal defenses, but also to harness a human enzyme—paradoxically, one normally used to destroy RNA—to enhance their disease-causing abilities. A team of scientists led by Jeffrey Kieft at the University of Colorado at Denver found that flaviviruses accomplish both feats by bending and twisting a small part of their RNA into a knot-like structure.
The scientists set out to learn more about this unusual ability. First, they determined the detailed, three-dimensional architecture of the convoluted flaviviral RNA. Then, they examined several different variations of the RNA. In doing so, they pinpointed parts that are critical for forming the knot-like shape. If researchers can find a way to prevent the RNA from completing its potentially dangerous twist, they’ll be a step closer to developing a treatment for flaviviral diseases, which affect more than 100 million people worldwide.
This work also was supported by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute.
This image may look complicated, but it tells a fairly straightforward tale about basic research: Learning more about basic life processes can pave the way for medical and other advances.
In this example, researchers led by Matthew Disney of the Scripps Research Institute’s Florida campus focused on better understanding the structural underpinnings of myotonic dystrophy type 2, a relatively rare, inherited form of adult-onset muscular dystrophy. While this work is still in the preliminary stages, it may hold potential for someday treating the disorder.
Some 300,000 NIH-funded scientists are working on projects aimed at improving disease diagnosis, treatment and prevention, often through increasing understanding of basic life processes.
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What looks like a colorful pattern produced as light enters a kaleidoscope is an image of a cell infected with respiratory syncytial virus (RSV) illuminated by a new imaging technology. Although relatively harmless in most children, RSV can lead to bronchitis and pneumonia in others. Philip Santangelo of the Georgia Institute of Technology and Emory University, along with colleagues nationwide, used multiply-labeled tetravalent RNA imaging probes (MTRIPS) to observe the entry, assembly and replication of RSV inside a living cell. Once introduced into RSV-plagued cells, the MTRIPS latched onto the viral RNA (in the image, red) without altering the level of infectivity. This led to fluorescent RSV viral particles that let the researchers track the viral RNA in host cells and better understand what the virus was doing. The knowledge gained from this new technique might aid in the development of RSV antiviral drugs and possibly a vaccine. Scientists could also one day use the imaging approach to study other RNA viruses, such as the flu and Ebola.
Georgia Tech News Release
In this video, Emad Tajkhorshid of the University of Illinois at Urbana-Champaign explains the molecular dance of ABC transporters, a family of molecular machines that utilize ATP to move substances across the cell membrane. Tajkhorshid and his team recently used computational methods to map the movements between two known structural models of MsbA, a bacterial version of a transporter in human cells that helps to export anti-cancer drugs. They then described the individual steps of the molecular motions during the transport cycle. Understanding the process at such a detailed level could suggest new targets for treating a range of diseases, including some drug-resistant cancers that often make more transporter proteins to kick out medications meant to kill them.
Myotonic dystrophy type 2 (DM2) is a relatively rare, inherited form of adult-onset muscular dystrophy that has no cure. It’s caused by a genetic defect in which a short series of nucleotides—the chemical units that spell out our genetic code—is repeated more times than normal. When the defective gene is transcribed, the resulting RNA repeat forms a hairpin-like structure that binds to and disables a protein called MBNL1.
Now, research led by Matthew Disney of The Scripps Research Institute (TSRI), Florida Campus, has revealed the detailed, three-dimensional structure of the RNA defect in DM2 and used this information to design small molecules that bind to the aberrant RNA. These designer molecules, even in small amounts, significantly improved disease-associated defects in a cellular model of DM2, and thus hold potential for reversing the disorder.
Drugs that target toxic RNA molecules associated with diseases such as DM2 are few and far between, as developing such compounds is technically challenging. The “bottom-up” approach that the scientists used to design potent new drug candidates, by first studying in detail how the RNA structure interacts with small molecules, is unconventional, noted Jessica Childs-Disney of TSRI, who was lead author of the paper with Ilyas Yildirim of Northwestern University. But it may serve as an effective strategy for pioneering the use of small molecules to manipulate disease-causing RNAs—a central focus of the Disney lab.
This work also was funded by NIH’s National Cancer Institute.
Like plants and animals, different types of E. coli thrive in different environments. Now, scientists can even predict which environments—such as the bladder, stomach or blood—are most amenable to the growth of various strains, including pathogenic ones. A research team led by Bernhard Palsson of the University of California, San Diego, accomplished this by using genome data to reconstruct the metabolic networks of 55 E. coli strains. The metabolic models, which identify differences in the ability to manufacture certain compounds and break down various nutrients, shed light on how certain E. coli strains become pathogenic and how to potentially control them. One approach could be depriving the deadly strains of the nutrients they need to survive in their niches. The researchers plan to use their new method to study other bacteria, such as those that cause staph infections.
This work also was funded by NIH’s National Cancer Institute.
University of California, San Diego News Release
In a statement on World AIDS Day 2013, NIH leaders wrote, “In the 25 years that have passed since the first annual commemoration of World AIDS Day, extraordinary scientific progress has been made in the fight against HIV/AIDS. That progress has turned an HIV diagnosis from an almost-certain death sentence to what is now for many, a manageable medical condition and nearly normal lifespan. We have come far, yet not far enough.”
One area of progress is in understanding the structural biology of HIV, the virus that causes AIDS. Capturing details about the virus’ shape has helped scientists better understand how HIV operates and pinpoint its Achilles’ heels. Recently, scientists got a closer look at two key pieces of the virus.
In one study, researchers developed the most detailed picture yet of Env, a three-segment protein on the HIV surface that allows the virus to infect cells. The work illuminated the complex process by which the protein assembles, undergoes radical shape changes during infection and interacts with neutralizing antibodies, which can block many strains of HIV from infecting human cells. The findings also may guide the development of HIV vaccines.
In another study, researchers created the best image yet of the cocoon-like container, or capsid, that carries HIV’s genome. Capsids have been difficult to study because individual imaging techniques had not produced high enough detail. By combining several cutting-edge imaging methods, the scientists pieced together the individual polygonal units of the capsid like a jigsaw puzzle to determine its structure in detail. Now that they know how HIV’s inner vessel looks, the research team is searching for its cracks—potential targets for drug development.
Sequencing the genomes of almost 7,000 organisms has identified more than 40 million proteins. But how do we figure out what all these proteins do? New results from an initiative led by John Gerlt of the University of Illinois suggest a possible method for identifying the functions of unknown enzymes, proteins that speed chemical reactions within cells. Using high-powered computing, the research team modeled how the structure of a mystery bacterial enzyme, HpbD, might fit like a puzzle piece into thousands of proteins in known metabolic pathways. Since an enzyme acts on other molecules, finding its target or substrate can shed light on its function. The new method narrowed HpbD’s candidate substrate down from more than 87,000 to only four. Follow-up lab work led to the actual substrate, tHypB, and determined the enzyme’s biological role. This combination of computational and experimental methods shows promise for uncovering the functions of many more proteins.
Every October, a few scientists receive a call from Sweden that changes their lives. From that day forward, they will be known as Nobel laureates. This year, five of the new Nobelists have received funding from NIGMS.
In physiology or medicine, NIGMS grantees James Rothman (Yale University) and Randy Schekman (University of California, Berkeley) were honored “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells.” They share the prize with Thomas C. Südhof of Stanford University.
Rothman and Schekman started out working separately and in different systems—Schekman in yeast and Rothman in reconstituted mammalian cells—and their conclusions validated each others’. It’s yet another example of the power of investigator-initiated research and the value of model systems.
The three Nobelists in chemistry are NIGMS grantees Martin Karplus (Harvard University), Michael Levitt (Stanford University) and Arieh Warshel (University of Southern California), who developed “multiscale models for complex chemical systems.” They used computational techniques to obtain, for the first time, detailed structural information about proteins and other large molecules. Because of that work, scientists around the world are now able to access, with a few keystrokes, highly accurate models of nearly 100,000 molecular structures. Studying these structures has advanced our understanding of countless diseases, pharmaceuticals and basic biological processes.