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 Antimicrobial substances identified in Komodo dragon blood
23.02.2017 | American Chemical Society

nachricht New Mechanisms of Gene Inactivation may prevent Aging and Cancer
23.02.2017 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)

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

From rocks in Colorado, evidence of a 'chaotic solar system'

23.02.2017 | Physics and Astronomy

'Quartz' crystals at the Earth's core power its magnetic field

23.02.2017 | Earth Sciences

Antimicrobial substances identified in Komodo dragon blood

23.02.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>