_|NATURE: Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor|_

[Giuseppe]

Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor

Nature 454, 177-182 (10 July 2008) | doi:10.1038/nature07082; Received 21 February 2008; Accepted 14 May 2008

Jeffrey E. Lee1, Marnie L. Fusco1, Ann J. Hessell1, Wendelien B. Oswald1, Dennis R. Burton1 & Erica Ollmann Saphire1
Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, Mail Drop IMM-2, La Jolla, California 92037, USA
Correspondence to: Erica Ollmann Saphire1 Correspondence and requests for materials should be addressed to E.O.S. (Email: erica@scripps.edu).

Ebola virus (EBOV) entry requires the surface glycoprotein (GP) to initiate attachment and fusion of viral and host membranes.

Here we report the crystal structure of EBOV GP in its trimeric, pre-fusion conformation (GP1+GP2) bound to a neutralizing antibody, KZ52, derived from a human survivor of the 1995 Kikwit outbreak.

Three GP1 viral attachment subunits assemble to form a chalice, cradled by the GP2 fusion subunits, while a novel glycan cap and projected mucin-like domain restrict access to the conserved receptor-binding site sequestered in the chalice bowl.

The glycocalyx surrounding GP is likely central to immune evasion and may explain why survivors have insignificant neutralizing antibody titres.

KZ52 recognizes a protein epitope at the chalice base where it clamps several regions of the pre-fusion GP2 to the amino terminus of GP1.

This structure provides a template for unravelling the mechanism of EBOV GP-mediated fusion and for future immunotherapeutic development.
-
http://www.nature.com/nature/journa...l;jsessionid=261CD6DA0D6229B5F366BACEFFF28667
------

 

[Giuseppe]

Re: _|NATURE: Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor|_

Scripps research scientists reveal key structure from ebola virus

Breakthrough findings point to targets for drugs and vaccines

Described in the July 10, 2008 issue of the journal Nature, the research reveals the shape of the Ebola virus spike protein, which is necessary for viral entry into human cells, bound to an immune system antibody acting to neutralize the virus.

The structure provides a major step forward in understanding how the deadly virus works, and may be useful in the development of potential Ebola virus vaccines, or treatments for those infected.

"Much about Ebola virus is still a mystery," says Erica Ollmann Saphire, the Scripps Research scientist who led the five-year effort. "However, this structure now reveals how this critical piece of the virus is assembled and, importantly, identifies vulnerable sites that we can exploit."

There is currently no cure for Ebola hemorrhagic fever.

The virus is spread when people come into contact with the bodily fluids of someone who is already infected. Most ultimately die from a combination of dehydration, massive bleeding, and shock.

The best treatment consists of administering fluids and taking protective measures to ensure containment, like isolating the patient and washing sheets with bleach.

The breakthrough described in the Nature article, though, provides hope that one day modern medicine will have more to offer.

The structure of the antibody together with the viral glycoprotein helps reveal the mechanisms by which the molecules assemble on the viral surface and helps explain how the pathogen evades and exploits the human immune system.

The structure also provides a guide for the design of drugs and vaccines to block this protein, potentially preventing disease and death.

The new research was made possible by an antibody isolated by Dennis Burton, a Scripps Research professor and one of the study's coauthors.

The antibody?shown bound to the Ebola virus spike protein in the current research?was derived from bone marrow of one of the few survivors of the 1995 Ebola outbreak in Kikwit, a city in the southwestern part of the Democratic Republic of Congo.

The Kikwit outbreak was particularly deadly, with a higher than 90 percent mortality rate for those infected.

In addition to its importance for Ebola, the new research has broader implications for the study of viruses in general.

"Structures of the native, oligomeric forms of viral glycoproteins as they exist on the viral surface are exceedingly difficult to achieve and thus exceedingly rare," notes Ollmann Saphire.

"This structure now provides templates by which researchers studying other viruses could try to understand how their virus's surface protein is assembled and neutralized by an antibody."

###
In addition to Ollmann Saphire, the article, "Structure of the trimeric, prefusion Ebola virus glycoprotein in complex with a neutralizing antibody from a human survivor," was authored by Jeffrey E. Lee, Marnie L. Fusco, Ann J. Hessell, Wendelien B. Oswald, and Dennis R. Burton at The Scripps Research Institute.

Support for the research was provided by grants from the National Institutes of Health, a Career Award from the Burroughs Wellcome Fund, and a fellowship from the Canadian Institutes of Health Research.

About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus by 2009.
-
http://www.eurekalert.org/pub_releases/2008-07/sri-srs070908.php
------

 

[Sally Furniss]

Re: _|NATURE: Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor|_

Ebola Protein Offers Clues for Vaccine, Drugs to Combat Virus
By Simeon Bennett


<!-- WARNING: #foreach: $wnstory.ATTS: null at /bb/data/web/templates/webmacro_en/washingtonstory.wm:266.2 --> <!-- WARNING: #foreach: $wnstory.ATTS: null at /bb/data/web/templates/webmacro_en/washingtonstory.wm:280.19 --> July 9 (Bloomberg) -- Ebola, a highly contagious virus that kills many of those infected within a week, has a protein that may point the way to drugs and vaccines, according to a study published today in the journal Nature.



Seen for the first time, the so-called glycoprotein is part of a structure the virus uses to enter healthy human cells. Researchers at the Scripps Research Institute in La Jolla, California, said by revealing the protein's shape and understanding how it works, they have exposed chinks in Ebola's armor that could be targeted for treatment.



``Much about Ebola virus is still a mystery,'' said Erica Ollmann Saphire, who led the research, in an e-mailed statement. ``This structure now reveals how this critical piece of the virus is assembled and, importantly, identifies vulnerable sites that we can exploit,'' she said.



There's no specific treatment or vaccine for Ebola, which kills 50 to 90 percent of people who contract it, according to the World Health Organization. The latest outbreak of the disease, which was confirmed by Ugandan health officials in November, was Africa's worst in five years.



More than 1,850 human cases, including 1,200 deaths, have been recorded since Ebola was first identified more than three decades ago in Sudan and the Democratic Republic of Congo. The virus causes high fevers, diarrhea and vomiting and often leads to severe internal bleeding.



Clues from Survivor



Ollmann Saphire and colleagues studied a virus sample isolated from a survivor of a 1995 outbreak in the Democratic Republic of the Congo. The virus was attached to a so-called neutralizing antibody that was fighting it. While research has shown the antibody protects rodents from Ebola, a study last year found it didn't work in monkeys.



By examining which parts of the virus were attached to the antibody, the scientists exposed its weaknesses, providing clues for future research.



They also discovered some parts of the virus that help it evade the body's immune system are similar in structure to parts of the HIV and Epstein-Barr viruses, suggesting Ebola may help scientists understand why some diseases manage to avoid the body's defenses.



Companies including Leiden, Netherlands-based Crucell NV and Alnylam Pharmaceuticals Inc, based in Cambridge, Massachusetts, are seeking to develop vaccines against Ebola.



To contact the reporter on this story: Simeon Bennett in Singapore at sbennett9@bloomberg.net


http://www.bloomberg.com/apps/news?pid=washingtonstory&sid=aFmlXd5xe_HQ