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 Complete skin regeneration system of fish unraveled
24.04.2018 | Tokyo Institute of Technology

nachricht Scientists generate an atlas of the human genome using stem cells
24.04.2018 | The Hebrew University of Jerusalem

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: BAM@Hannover Messe: innovative 3D printing method for space flight

At the Hannover Messe 2018, the Bundesanstalt für Materialforschung und-prüfung (BAM) will show how, in the future, astronauts could produce their own tools or spare parts in zero gravity using 3D printing. This will reduce, weight and transport costs for space missions. Visitors can experience the innovative additive manufacturing process live at the fair.

Powder-based additive manufacturing in zero gravity is the name of the project in which a component is produced by applying metallic powder layers and then...

Im Focus: Molecules Brilliantly Illuminated

Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.

Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Quantum Technology for Advanced Imaging – QUILT

24.04.2018 | Information Technology

AWI researchers measure a record concentration of microplastic in arctic sea ice

24.04.2018 | Earth Sciences

Complete skin regeneration system of fish unraveled

24.04.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>