Scientists pinpoint shape-shifting mechanism critical to protein signaling

In a joint study, scientists from the California and Florida campuses of The Scripps Research Institute have shown that changes in a protein's structure can change its signaling function and they have pinpointed the precise regions where those changes take place.

The new findings could help provide a much clearer picture of potential drugs that would be both effective and highly specific in their biological actions.

The study, led by Patrick Griffin of Scripps Florida and Raymond Stevens of Scripps California, was published in a recent edition of the journal Structure.

The new study focuses on the ß2-adrenergic receptor, a member of the G protein-coupled receptor family. G protein-coupled receptors convert extracellular stimuli into intracellular signals through various pathways. Approximately one third of currently marketed drugs (including for diabetes and heart disease) target these receptors.

Scientists have known that when specific regions of the receptor are activated by neurotransmitters or hormones, the structural arrangement (conformation) of the receptor is changed along with its function.

"While it's accepted that these receptors adopt multiple conformations and that each conformation triggers a specific type of signaling, the molecular mechanism behind that flexibility has been something of a black box," said Griffin, who is chair of the Scripps Research Department of Molecular Therapeutics and director of the Scripps Florida Translational Research Institute. "Our findings shed significant light to it."

The study describes in structural detail the various regions of the receptor that are involved in the changes brought about by selective ligands (ligands are molecules that bind to proteins to form an active complex), which, like a rheostat, run the gamut among activating the receptor, shutting it down, and reversing its function, as well as producing various states in between.

To achieve the results described in the study, the team used hydrogen-deuterium (HDX) mass spectrometry to measure the impact of interaction of various functionally selective ligands with the ß2-adrenergic receptor. A mass spectrometer determines the mass of fragments from the receptor by measuring the mass-to-charge ratio of their ions. HDX has been used to examine changes in the shape of proteins and how these shape changes relate to protein function. The approach is often used to characterize protein-protein interactions that are critical for signal transduction in cells and to study protein-folding pathways that are critical to cell survival.

"At this early stage in understanding GPCR structure and function, it is important to view the entire receptor in combination with probing very specific regions," said Stevens, who is a professor in the Scripps Research Department of Molecular Biology. "Hydrogen-deuterium exchange mass spectrometry has the right timescale and resolution to asked important questions about complete receptor conformations in regards to different pharmacological ligand binding. The HDX data combined with the structural data emerging will really help everyone more fully understand how these receptors work."

"Using the HDX technology we can study the intact receptor upon interaction with ligands and pinpoint regions of the receptor that have undergone change in position or flexibility," Griffin said. "By studying a set of ligands one can start to develop patterns that are tied to activation of the receptor or shutting it down. Once we get a picture of what a functional ligand looks like, it might be possible to develop a drug to produce a highly selective therapeutic effect."

More information: "Ligand-Dependent Perturbation of the Conformational Ensemble for the GPCR b2 Adrenergic Receptor Revealed by HDX," Structure.

Provided by The Scripps Research Institute (news : web)

Need for new magnet materials drives ORNL research

Increasing demand and a shrinking supply of rare earth elements for magnets creates a perfect opportunity for a research team from Oak Ridge National Laboratory and the University of Minnesota. The goal is to create a recipe for a replacement that doesn't use scarce ingredients.

"Worldwide demand for rare earths is expected to exceed supply by some 40,000 tons annually by the end of this decade," said Larry Allard, a researcher in ORNL's Materials Science and Technology Division. "In the past, 95 percent of that material has been supplied to the world by China, but in recent years China has begun limiting exports and by 2015 is expected to become a net importer."

The prospect of not having enough rare earth elements such as neodymium and dysprosium for magnets looms large for industries that need them for products we count on every day.

Most people never give it a second thought, but magnets are used in everything from the motors that power hybrid vehicles and electric windows to windmills, computers and hundreds of items that touch our lives every day. The traction drive components of a Toyota Prius, for example, use about 2 pounds of magnet materials while a 3-megawatt windmill uses 550 pounds. Today's automobiles and light trucks each use between 70 and 150 magnets to operate the speedometer, odometer, gas gauge, antilock brake systems, air bag sensors, fuel pumps and dozens of other systems.

In the home, magnets are even more common as they are found in door chimes, security systems, personal computers, printers, telephones, furnaces and air conditioning systems, garage door openers, refrigerators, freezers, workshop tools, hair dryers and electric shavers. It's difficult to imagine a world with no magnets. From an economics and national security perspective, it would be catastrophic.

That's why researchers like Allard, Edgar Lara-Curzio and Mike Brady of ORNL and Jian-Ping Wang of the University of Minnesota are focused on developing magnets made from abundant and inexpensive materials. Of specific interest is an iron nitride compound with a specific phase that potentially exhibits the highest saturation magnetization ever reported for a material.

"This is a critical parameter related to the highest degree to which a material can be magnetized," said Allard, who noted that this particular iteration of the iron-nitrogen compound has values up to 18 percent higher than the best commercial alloy, iron cobalt. The problem is that this material is metastable and exhibits relatively low coercivity, which means it can be demagnetized easily. The best permanent magnets - such as those made of neodymium-iron-boride - score high in these areas.

Working with Wang, Allard, Lara-Curzio and Brady will devise a method of producing this pure phase iron nitride compound and use specialized modeling methods to better understand the role of alloying additions that might stabilize the material so it retains its magnetic properties. Through their efforts, the researchers hope to better understand the magnetic behavior of the "alpha double prime" phase by correlating microstructure at the atomic level to processing and magnetic behavior.

Once researchers have answered these questions, their goal is to make bulk quantities of the material and move toward their ultimate goal of replacing neodymium-iron-boride magnets for automotive and other energy technology uses. This work with the University of Minnesota builds on previous work with Wang in which ORNL researchers were able to characterize iron nitride films with demonstrated potential. Allard noted that the Spallation Neutron Source made it possible to perform polarized neutron reflectometry, a test performed by Valeria Lauter to determine magnetic property.

In a separate effort, ORNL's David Parker hopes to computationally screen dozens of materials and then mix elements that emerge as promising candidates in a way to create a compound that will behave like rare earth elements. This material must also be scalable, retain its magnetic properties under varying conditions and meet cost-performance criteria. Parker noted that often the compounds identified as having desirable properties consist of elements with greatly differing melting points, stabilities and other traits and can prove very difficult to controllably manufacture. That's where ORNL's unique capabilities come into play.

"We have a suite of conventional and novel processing approaches to try to make the computationally predicted compounds, including a range of powder consolidation and gas reaction approaches," said Parker, who noted that there's nothing "sacred" about rare earth elements.

"Their main advantage is that due to their large nuclear charge, spin-orbit coupling is very strong and serves to fix the magnetization direction of the unpaired electrons," Parker said. "Other heavy elements may play the same role."

By employing strategic computational screening and ORNL's specialized microscopy and characterization skills, Allard and Parker believe they can make great strides toward solving a problem of national importance.

Provided by Oak Ridge National Laboratory (news : web)

Old fruit peel are the new healthy snacks

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A snapshot of Fruit-Peelo. Credit: UiTM

Japanese food researchers Noriham Abdullah, Marina Zulkifli, Mohd Hilmi Hassan, Wan Nur Zahidah Wan Zainon and Nur Ilmiah Alimin have developed a new healthy snack out of fruit peels to fulfil a growing need for fast, on-the-go health food.

There is a growing body of evidence suggesting health conscious consumers are becoming more experimental in selecting their healthier snacks alternatives. In response to this, a team of researchers from the Faculty of Applied Sciences used cheap and abundant agricultural by-products, such as mango and guava peels, to produce a leathery, bite size snacks called Fruity-Peelo.

Fruit peels contain high levels of polyphenols, carotenoids and other bioactive compounds which offer various health benefits. In addition, utilisation of such by-products is a promising measure from an environmental as well as an economic point of view.

Dr. Noriham Abdullah, the lead researcher, says that Fruity-Peelo is a tasty convenience snack with long shelf life that contains healthy compounds such as antioxidants, dietary fibres and Vitamin C.

The growing concerns over climbing obesity levels, combined with efforts to rejuvenate the image of the on-the-go healthy food options, have further improved Fruity Peelo’s prospect to fulfil a growing demand for convenience snacks that are healthy, quick and unique.

Provided by Universiti Teknologi MARA

Pair claim they can make ammonia to fuel cars for just 20 cents per liter

Fleming of SilverEagles Energy and Tim Maxwell from Texas Tech University, say they have developed a way to make ammonia that is cheap enough so that it could be used as fuel for cars. If their claims turn out to be true, many consumers might consider switching over because ammonia, when burned in an engine, emits nothing but nitrogen and water vapor out the tailpipe. And if that’s not enough incentive, they claim they can make the ammonia for just 20 cents a liter (approximately 75 cents a gallon).

The secret to their low cost estimates actually lie in their newly developed method for making hydrogen, which they use to make their ammonia. They say that by using a new kind of transformer that Fleming built, they can reduce the number of cells necessary for electrolysis to such a degree that they can produce hydrogen at almost half the cost of traditional electrolysis methods.

To make the ammonia, the hydrogen produced is pumped into a compression chamber where a piston squeezes it, causing it to heat up; in this case to 400C°. The result is then allowed to escape into another compartment where a reaction is set off by an iron oxide catalyst. This makes the hydrogen grow even hotter to the point where it begins creating ammonia. The ammonia and leftover hydrogen is then allowed to cool down and decompress in yet a third compartment, and in so doing causes another piston to move back and forth creating energy that is fed back into the system to help lower electric consumption. Then, the ammonia is chilled to -75C° and pumped into a tank for use.

Cars already on the road can use ammonia as an additive without modification (up to 10%) and flex cars could be, according to Fleming, easily modified to use ammonia in conjunction with ethanol, allowing for a mixture of 85% ammonia.

This is all still new technology of course, and apparently no one else has yet verified the claims of the duo, so until that happens, everyone will just have to wait and see if everything they say pans out. One thing not mentioned is the smell; the strong odor of gasoline at service stations is bad enough, it’s difficult to imagine the exceedingly noxious odor of ammonia permeating the air of such places instead.

More information: via Newscientist

 

Artificial light-harvesting method achieves 100% energy transfer efficiency

In an attempt to mimic the photosynthetic systems found in plants and some bacteria, scientists have taken a step toward developing an artificial light-harvesting system (LHS) that meets one of the crucial requirements for such systems: an approximately 100% energy transfer efficiency. Although high energy transfer efficiency is just one component of the development of a useful artificial LHS, the achievement could lead to clean solar-fuel technology that turns sunlight into chemical fuel.

The researchers, led by Shinsuke Takagi from the Tokyo Metropolitan University and PRESTO of the Japan Science and Technology Agency, have published their study on their work toward an artificial LHS in a recent issue of the Journal of the American Chemical Society.

“In order to realize an artificial light-harvesting system, almost 100% efficiency is necessary,” Takagi told PhysOrg.com. “Since light-harvesting systems consist of many steps of energy transfer, the total energy transfer efficiency becomes low if the energy transfer efficiency of each step is 90%. For example, if there are five energy transfer steps, the total energy transfer is 0.9 x 0.9 x 0.9 x 0.9 x 0.9 = 0.59. In this way, an efficient energy transfer reaction plays an important role in realizing efficient sunlight collection for an artificial light-harvesting system.”

As the researchers explain in their study, a natural LHS (like those in purple bacteria or plant leaves) is composed of regularly arranged molecules that efficiently collect sunlight and carry the excitation energy to the system’s reaction center. An artificial LHS (or “artificial leaf”) attempts to do the same thing by using functional dye molecules.

Building on the results of previous research, the scientists chose to use two types of porphyrin dye molecules for this purpose, which they arranged on a clay surface. The molecules’ tendency to aggregate or segregate on the clay surface made it challenging for the researchers to arrange the molecules in a regular pattern like their natural counterparts.

“A molecular arrangement with an appropriate intermolecular distance is important to achieve nearly 100% energy transfer efficiency,” Takagi said. “If the intermolecular distance is too near, other reactions such as electron transfer and/or photochemical reactions would occur. If the intermolecular distance is too far, deactivation of excited dye surpasses the energy transfer reaction.”

In order to achieve the appropriate intermolecular distance, the scientists developed a novel preparation technique based on matching the distances between the charged sites in the porphyrin molecules and the distances between negatively charged (anionic) sites on the clay surface. This effect, which the researchers call the “Size-Matching Rule,” helped to suppress the major factors that contributed to the porphyrin molecules’ tendency to aggregate or segregate, and fixed the molecules in an appropriate uniform intermolecular distance. As Takagi explained, this strategy is significantly different than other attempts at achieving molecular patterns.

“The methodology is unique,” he said. “In the case of usual self-assembly systems, the arrangement is realized by guest-guest interactions. In our system, host-guest interactions play a crucial role for realizing the special arrangement of dyes. Thus, by changing the host material, it is possible to control the molecular arrangement of dyes on the clay surface.”

As the researchers demonstrated, the regular arrangement of the molecules leads to an excited energy transfer efficiency of up to 100%. The results indicate that porphyrin dye molecules and clay host materials look like promising candidates for an artificial LHS.

“At the present, our system includes only two dyes,” Takagi said. “As the next step, the combination of several dyes to adsorb all sunlight is necessary. One of the characteristic points of our system is that it is easy to use several dyes at once. Thus, our system is a promising candidate for a real light-harvesting system that can use all sunlight. We believe that even photochemical reaction parts can be combined on the same clay surface. If this system is realized and is combined with a photochemical reaction center, this system can be called an ‘inorganic leaf.’”

More information: Yohei Ishida, et al. “Efficient Excited Energy Transfer Reaction in Clay/Porphyrin Complex toward an Artificial Light-Harvesting System.” Journal of the American Chemical Society. DOI:10/1021/ja204425u