Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New approach studying protein structure could advance drug development

09.12.2004


Developed by biologists at Argonne National Lab



Structural changes in proteins can now be seen in increased detail, using a new application of an existing technique. The application, developed at the U.S. Department of Energy’s Argonne National Laboratory, could help produce lead drugs for disease therapy.

In research published in Chemistry and Biology, the scientists report the use of wide angle X-ray scattering (WAXS), an X-ray diffraction technique that has previously been used to determine the crystalline structures of polymers. The biologists adapted this materials science technique to study ligand-induced structural changes in proteins. Ligands are molecules that can cause the creation of complex compounds in protein structure. The results Argonne scientists achieved using WAXS are comparable to the already accepted predictions of protein structures provided by X-ray crystallography, and are easier and quicker to obtain. The results also show promise for using WAXS as a reliable and high-speed tool for lead drug identification.


WAXS has the potential to identify medicinal drugs that can bind to target proteins and to determine how effective drugs are at binding to and modifying their targeted proteins. The technique is sensitive enough to tell the difference between a ligand that’s just sticking to the surface of a protein (a drug that may have no effect) and a ligand that’s actually changing the structure (a drug that is more likely to be effective). In the past, detecting this difference required the use of several techniques combined. No other previous technique has been able to distinguish the difference on its own, or as quickly.

"Wide angle X-ray scattering provides a real tool for identifying lead drugs," said co-author Lee Makowski of Argonne’s Biosciences Division, "It will identify a molecule that’s good enough to be developed as a drug."

The researchers believe WAXS will allow scientists to study more protein-ligand interactions at a faster and cheaper rate than the existing laborious and expensive X-ray crystallography. "The data collection only takes a couple of minutes," said Makowski, "So theoretically an industrial pipeline could be set up that would only be limited by a few minutes per protein-small molecule interaction." Functional cell-based assays (which are needed for other methods) currently take weeks, if not months to complete--causing a bottleneck in data collection and analysis.

Furthermore, high quality crystal structures are tough to attain, and only a limited number of proteins have documented crystal structures of the protein with and without a ligand present. "There is no other technique like this out there," said co-author Diane Rodi from Argonne’s Biosciences Division, "You can see more detailed changes that take place in protein-ligand interactions in solution than you can with any other technique. And more protein-ligand interactions can be tested."

No previous available technique is able to show the magnitude of protein structure change in the absence of a crystal structure. Small angle X-ray scattering (SAXS) is able to show the size and shape of the protein, but does not show details about the change. Circular dichroism spectroscopy (a method that provides structural information on many types of biological macromolecules) doesn’t show the level of detailed changes WAXS provides.

WAXS does not require any crystallization, but uses the same X-ray scattering procedure as crystallography. The technique involves placing the protein and ligand in a water-based solution and then placing this solution in the path of an X-ray beam. The resulting X-ray scattering pattern reveals information about the detailed structure of the protein-ligand complex, which can then be contrasted with a scattering pattern of the protein alone.

The researchers at Argonne tested four proteins plus and minus their corresponding ligands using WAXS, which uses the intense X-ray beams at the BioCAT facility in the Advanced Photon Source. The proteins were chosen based upon the best structures available from the Protein Data Bank that had already been observed with and without ligands using X-ray crystallography.

"We chose proteins that already had crystal structures so that we could assess just how good the WAXS technique is," said lead-author Bob Fischetti, of both Argonne’s Advanced Photon Source and Biosciences Division, "And of course we wanted to convince people that what we were seeing is real."

The tested proteins displayed changes that directly corresponded to those documented from the crystal structures, proving the observations were real and validating the method as a potential drug discovery tool.

The other author on the report, in addition to Fischetti, Rodi and Makowski is David B. Gore (BioCAT, Advanced Photon Source, Argonne).

The researchers have submitted a grant proposal request to the National Institutes of Health for possible funding of future studies with WAXS.

Catherine Foster | EurekAlert!
Further information:
http://www.anl.gov

More articles from Life Sciences:

nachricht More genes are active in high-performance maize
19.01.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht How plants see light
19.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Let the good tubes roll

19.01.2018 | Materials Sciences

How cancer metastasis happens: Researchers reveal a key mechanism

19.01.2018 | Health and Medicine

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>