Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

After 40 years, the first complete picture of a key flu virus machine

20.11.2014

If you planned to sabotage a factory, a recon trip through the premises would probably be much more useful than just peeping in at the windows.

Scientists looking to understand – and potentially thwart – the influenza virus have now gone from a similar window-based view to the full factory tour, thanks to the first complete structure of one of the flu virus’ key machines.


The complete structure allows researchers to understand how the polymerase uses host cell RNA (red) to kick-start the production of viral messenger RNA. Credit: EMBL/P.Riedinger

The structure, obtained by scientists at the European Molecular Biology Laboratory (EMBL) in Grenoble, France, allows researchers to finally understand how the machine works as a whole. Published today in two papers in Nature, the work could prove instrumental in designing new drugs to treat serious flu infections and combat flu pandemics.

The machine in question, the influenza virus polymerase, carries out two vital tasks for the virus. It makes copies of the virus’ genetic material – the viral RNA – to package into new viruses that can infect other cells; and it reads out the instructions in that genetic material to make viral messenger RNA, which directs the infected cell to produce the proteins the virus needs.

Scientists – including Cusack and collaborators – had been able to determine the structure of several parts of the polymerase in the past. But how those parts came together to function as a whole, and how viral RNA being fed in to the polymerase could be treated in two different ways remained a mystery.

“The flu polymerase was discovered 40 years ago, so there are hundreds of papers out there trying to fathom how it works. But only now that we have the complete structure can we really begin to understand it,” says Stephen Cusack, head of EMBL Grenoble, who led the work.

Using X-ray crystallography, performed at the European Synchrotron Radiation Facility (ESRF) in Grenoble, Cusack and colleagues were able to determine the atomic structure of the whole polymerase from two strains of influenza: influenza B, one of the strains that cause seasonal flu in humans, but which evolves slowly and therefore isn’t considered a pandemic threat; and the strain of influenza A – the fast-evolving strain that affects humans, birds and other animals and can cause pandemics – that infects bats.

“The high-intensity X-ray beamlines at the ESRF, equipped with state-of-the-art Dectris detectors, were crucial for getting high quality crystallographic data from the weakly diffracting and radiation sensitive crystals of the large polymerase complex,” says Cusack. “We couldn’t have got the data at such a good resolution without them”.

The structures reveal how the polymerase specifically recognises and binds to the viral RNA, rather than just any available RNA, and how that binding activates the machine. They also show that the three component proteins that make up the polymerase are very intertwined, which explains why it has been very difficult to piece together how this machine works based on structures of individual parts.

Although the structures of both viruses’ polymerases were very similar, the scientists found one key difference, which showed that one part of the machine can swivel around to a large degree. That ability to swivel explains exactly how the polymerase uses host cell RNA to kick-start the production of viral proteins. The swivelling component takes the necessary piece of host cell RNA and directs it into a slot leading to the machine’s heart, where it triggers the production of viral messenger RNA.

Now that they know exactly where each atom fits in this key viral machine, researchers aiming to design drugs to stop influenza in its tracks have a much wider range of potential targets at their disposal – like would-be saboteurs who gain access to the whole production plant instead of just sneaking looks through the windows. And because this is such a fundamental piece of the viral machinery, not only are the versions in the different influenza strains very similar to each other, but they also hold many similarities to their counterparts in related viruses such as lassa, hanta, rabies or ebola.

The EMBL scientists aim to explore the new insights this structure provides for drug design, as well as continuing to try to determine the structure of the human version of influenza A, because although the bat version is close enough that it already provides remarkable insights, ultimately fine-tuning drugs for treating people would benefit from/require knowledge of the version of the virus that infects humans. And, since this viral machine has to be flexible and change shape to carry out its different tasks, Cusack and colleagues also want to get further snapshots of the polymerase in different states.

“This doesn’t mean we now have all the answers,” says Cusack, “In fact, we have as many new questions as answers, but at least now we have a solid basis on which to probe further.”


The work was carried out on the ESRF’s ID23-1 beamline. The study was conducted within the joint Unit of Virus-Host Cell Interactions (UVHCI), a collaboration between EMBL, the Centre National de la Recherche Scientifique (CNRS) and the Grenoble University Joseph Fourier. The work was funded by an Advanced Investigator grant from the European Research Council (ERC) to Stephen Cusack and by the EU-funded project FluPHARM.


Published online in Nature on 19 November 2014. DOI: 10.1038/nature14008 and DOI: 10.1038/nature14009.
For images, video and more information please visit: www.embl.org/press/2014/141119_Grenoble

Policy regarding use

EMBL press and picture releases including photographs, graphics and videos are copyrighted by EMBL. They may be freely reprinted and distributed for non-commercial use via print, broadcast and electronic media, provided that proper attribution to authors, photographers and designers is made.

Sonia Furtado Neves
EMBL Press Officer & Deputy Head of Communications
Meyerhofstr. 1, 69117 Heidelberg, Germany
Tel.: +49 (0)6221 387 8263
Fax: +49 (0)6221 387 8525
sonia.furtado@embl.de
http://s.embl.org/press

Sonia Furtado Neves | EMBL Press
Further information:
http://www.embl.de/aboutus/communication_outreach/media_relations/2014/141119_Grenoble/#

More articles from Life Sciences:

nachricht Scientists spin artificial silk from whey protein
24.01.2017 | Deutsches Elektronen-Synchrotron DESY

nachricht Choreographing the microRNA-target dance
24.01.2017 | UT Southwestern Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Scientists spin artificial silk from whey protein

X-ray study throws light on key process for production

A Swedish-German team of researchers has cleared up a key process for the artificial production of silk. With the help of the intense X-rays from DESY's...

Im Focus: Quantum optical sensor for the first time tested in space – with a laser system from Berlin

For the first time ever, a cloud of ultra-cold atoms has been successfully created in space on board of a sounding rocket. The MAIUS mission demonstrates that quantum optical sensors can be operated even in harsh environments like space – a prerequi-site for finding answers to the most challenging questions of fundamental physics and an important innovation driver for everyday applications.

According to Albert Einstein's Equivalence Principle, all bodies are accelerated at the same rate by the Earth's gravity, regardless of their properties. This...

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...

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

Breaking the optical bandwidth record of stable pulsed lasers

24.01.2017 | Physics and Astronomy

Choreographing the microRNA-target dance

24.01.2017 | Life Sciences

Spanish scientists create a 3-D bioprinter to print human skin

24.01.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>