Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

TSRI scientists pinpoint Ebola's weak spots

09.08.2016

New study illuminates structure of mystery protein

Scientists at The Scripps Research Institute (TSRI) now have a high-resolution view of exactly how the experimental therapy ZMapp targets Ebola virus.


The Scripps Research team succeeded in showing how experimental therapy ZMapp targets the Ebola virus, here targeting the virus's GP protein.

Image courtesy of Andrew Ward and Jesper Pallesen

The new study is also the first to show how an antibody in the ZMapp "drug cocktail" targets a second Ebola virus protein, called sGP, whose vulnerable spots had previously been unknown.

"This sGP protein is tremendously important," said TSRI Professor Erica Ollmann Saphire, who co-led the study with TSRI Associate Professor Andrew Ward. "This is the roadmap we need to target the right molecules in infection."

"Determining the proper balance in targeting these two Ebola proteins will be key to building improved therapeutics," added Ward.

The study was published August 8, 2016 in the journal Nature Microbiology.

Zooming in on ZMapp

Scientists need detailed images of Ebola virus's molecular structure. Like enemy reconnaissance, structures can show where Ebola is vulnerable and how medical treatments can neutralize it.

TSRI scientists are harnessing an imaging technique called cryo-electron microscopy (in which a sample is pelted with electrons) to create high-resolution, 3-D images of Ebola virus and the antibodies that fight it.

"We're at the cutting edge of our ability to resolve high-resolution protein complexes," said TSRI Research Associate C. Daniel Murin, co-first author of the new study with TSRI Research Associate Jesper Pallesen.

In the new study, the researchers used cryo-electron microscopy to see exactly how Ebola virus interacts with the three antibodies in the ZMapp experimental therapy produced by Mapp Biopharmaceutical, also a study collaborator.

The researchers had imaged these interactions at a low resolution in a 2014 study, but the new study revealed substantially more details, including the exact angles the antibodies use to approach the molecule on the surface of the virus, termed its surface glycoprotein (GP), and the individual amino acid contact points at which the antibodies bind GP. This information provides new clues to researchers trying to make the antibodies even more effective.

"The three components of ZMapp, now resolved at high-resolution, can be further engineered in a structure-based manner for improved potency," said Ward.

Solving an Elusive Structure

Next, the researchers took a closer look at one of the three antibodies that make up ZMapp, called 13C6. This antibody is unique because it can also target the soluble Ebola protein sGP.

sGP's role in infection is a mystery. Ebola virus makes the protein profusely, indicating that it is important, but then sGP appears just to float in a person's blood serum. One theory is that sGP may be essential in the natural host "reservoir."

"Eighty to ninety percent of what Ebola virus makes in infection is this shed molecule," said Saphire. "It's like a smoke screen, and we need to know where it is similar to our target GP and where it is different."

To add to the mystery, Ebola makes GP and sGP using the same gene. A small difference in the way the gene is read changes how the molecules are shaped and changes their roles.

One obstacle to understanding sGP is that it is too small to be seen with cryo-electron microscopes. To solve this problem, the researchers added "bulk" by pairing sGP with antibodies, including 13C6. This allowed them to kill two birds with one stone--they could see sGP's structure while also studying how antibodies interact with it.

The new image shows the binding sites, or "epitopes," the antibody targets. "We can see hot spots on this virus that we can hit," said Pallesen.

This study is the latest research from the Viral Hemorrhagic Fever Consortium, an international partnership of research institutes led by Saphire. The researchers said collaboration with the consortium was key to this study, allowing scientists to share samples and data, including viral genetic sequences isolated from patients in the most recent Ebola outbreak.

###

In addition to Saphire, Ward, Murin and Pallesen, authors of the study, "Structures of Ebola virus GP and sGP in complex with therapeutic antibodies," [http://www.nature.com/articles/nmicrobiol2016128] were Natalia de Val, Christopher A. Cottrell, Kathryn M. Hastie, Hannah Turner and Marnie Fusco of TSRI; Kristian G. Andersen of TSRI and the Scripps Translational Science Institute; Andrew I. Flyak and James E. Crowe of Vanderbilt University and Larry Zeitlin of Mapp Biopharmaceutical.

This study was supported by the National Institutes of Health (NIH, grant R01 AI067927), the NIH's National Institute of Allergy and Infectious Diseases (grant U19AI109762 and U19AI109711) and the National Science Foundation.

Media Contact

Madeline McCurry-Schmidt
858-784-9254

 @scrippsresearch

http://www.scripps.edu 

Madeline McCurry-Schmidt | EurekAlert!

More articles from Life Sciences:

nachricht Not of Divided Mind
19.01.2017 | Hertie-Institut für klinische Hirnforschung (HIH)

nachricht CRISPR meets single-cell sequencing in new screening method
19.01.2017 | CeMM Forschungszentrum für Molekulare Medizin der Österreichischen Akademie der Wissenschaften

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

New Study Will Help Find the Best Locations for Thermal Power Stations in Iceland

19.01.2017 | Earth Sciences

Not of Divided Mind

19.01.2017 | Life Sciences

Molecule flash mob

19.01.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>