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 Study shines light on brain cells that coordinate movement
26.06.2017 | University of Washington Health Sciences/UW Medicine

nachricht New insight into a central biological dogma on ion transport
26.06.2017 | Aarhus University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Study shines light on brain cells that coordinate movement

26.06.2017 | Life Sciences

Smooth propagation of spin waves using gold

26.06.2017 | Physics and Astronomy

Switchable DNA mini-machines store information

26.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>