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 Warming ponds could accelerate climate change
21.02.2017 | University of Exeter

nachricht An alternative to opioids? Compound from marine snail is potent pain reliever
21.02.2017 | University of Utah

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Impacts of mass coral die-off on Indian Ocean reefs revealed

21.02.2017 | Earth Sciences

Novel breast tomosynthesis technique reduces screening recall rate

21.02.2017 | Medical Engineering

Use your Voice – and Smart Homes will “LISTEN”

21.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>