Zika: Defining the antigenic epitopes in the Zika virus envelope protein
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
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Technical Summary
Zika virus belongs to the flavivirus genus and has 58% amino acid sequence identity to
dengue virus. Flaviviruses are enveloped viruses with a lipid membrane surrounded by an
outer protein shell consisting of two structural, transmembrane glycoproteins, prM and E. In
mature and infectious flaviviruses, the E protein forms a continuous icosahedral protein shell,
which contains encompasses the cellular attachment interfaces, and all of the dominant
neutralization antibody epiotpes. Moreover, the E protein catalyzes the fusion of the viral
membrane to the host cell membrane, the critical step in cell entry that delivers the viral
genome into the cytoplasm. We previously determined the crystal structures of the E proteins
from various flaviviruses, including dengue virus, in the pre- and postfusion conformations.
These structures provided detailed maps of the antigenic landscape of the virus, and revealed
the molecular mechanism of membrane fusion. Here, we propose to harness our expertise
and apply the experimental approaches we established in our previous work on flaviviruses to
determine the atomic structure of the Zika virus E protein, how it assembles in virus
particles, and how it catalyzes membrane fusion during cell entry. By identifying the structure
and composition of the complete antigenic surface of Zika virus, this work will provide a
powerful framework for the design and production of preventative and therapeutic treatments
including therapeutic antibodies, subunit-based vaccines and virus cell-entry inhibitors.
dengue virus. Flaviviruses are enveloped viruses with a lipid membrane surrounded by an
outer protein shell consisting of two structural, transmembrane glycoproteins, prM and E. In
mature and infectious flaviviruses, the E protein forms a continuous icosahedral protein shell,
which contains encompasses the cellular attachment interfaces, and all of the dominant
neutralization antibody epiotpes. Moreover, the E protein catalyzes the fusion of the viral
membrane to the host cell membrane, the critical step in cell entry that delivers the viral
genome into the cytoplasm. We previously determined the crystal structures of the E proteins
from various flaviviruses, including dengue virus, in the pre- and postfusion conformations.
These structures provided detailed maps of the antigenic landscape of the virus, and revealed
the molecular mechanism of membrane fusion. Here, we propose to harness our expertise
and apply the experimental approaches we established in our previous work on flaviviruses to
determine the atomic structure of the Zika virus E protein, how it assembles in virus
particles, and how it catalyzes membrane fusion during cell entry. By identifying the structure
and composition of the complete antigenic surface of Zika virus, this work will provide a
powerful framework for the design and production of preventative and therapeutic treatments
including therapeutic antibodies, subunit-based vaccines and virus cell-entry inhibitors.
People |
ORCID iD |
Yorgo Modis (Principal Investigator) |
Publications
Prigozhin DM
(2016)
Flunarizine arrests hepatitis C virus membrane fusion.
in Hepatology (Baltimore, Md.)
Title | Scientific animation of dengue virus fusing with a host cell |
Description | Scientific animation of dengue virus invading with a host cell. See also: https://www.youtube.com/watch?v=nN1xJxXAptc |
Type Of Art | Film/Video/Animation |
Year Produced | 2019 |
Impact | Educational material has reached a broad audience (over 100,000 views on YouTube and PDS sites). |
URL | https://www.pbslearningmedia.org/resource/den08.sci.life.stru.dengue/dengue-virus-invades-a-cell/ |
Description | National Institutes of Health Oxford-Cambridge Scholars Program - studentship to Bridget Larman |
Amount | £192,000 (GBP) |
Organisation | National Institutes of Health (NIH) |
Sector | Public |
Country | United States |
Start | 08/2017 |
End | 08/2022 |
Description | Joint PhD research project on Zika virus as part of NIH Oxford-Cambridge Scholars Program |
Organisation | National Institute of Allergy and Infectious Diseases (NIAID) |
Country | United States |
Sector | Public |
PI Contribution | This partnership covers a joint research project being carried out by Bridget Larman as part of the NIH Oxford-Cambridge Scholars Program, in collaboration with Theodore Pierson and his group at the National Institute of Allergy and Infectious Diseases (NIAID) in the United States. I am serving as the joint PhD advisor to Bridget, who will spend half of her time in my group and half in Dr. Pierson's group. Dr. Pierson serves as Bridget's other joint PhD advisor. The aim of the project is to expand our understanding of the conformational dynamics in envelope glycoproteins within Zika virus particles and oligomeric protein assemblies. The project is being carried out as a collaboration between the Modis lab and the Pierson lab. Using techniques and the expertise from both labs Bridget is applying multiple approaches to explore the conformational dynamics of Zika virus. Specifically Bridget is establishing a method label specific sites on the Zika envelope protein using genetically-encoded non-canonical amino acids. During her time in my group, Bridget is purifying fluorescently labeled proteins to study their conformational dynamics using FRET and other biophysical approaches. |
Collaborator Contribution | During her time in Dr. Pierson's group, Bridget will apply the genetically-encoded labeling method she is currently developing in my group to study antibody binding and neutralization mechanisms. |
Impact | No outputs to report yet. Study is multidisciplinary: -chemical labeling by expansion of the genetic code (non-canonical amino acids) -biophysics -structural biology -virology -immunology |
Start Year | 2017 |
Description | Interview with Cambridge TV |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Media (as a channel to the public) |
Results and Impact | I was interviewed by Hollie Goodall on my research project on Zika virus and on receiving funding from the MRC, Wellcome Trust and the Newton Trust for this project. The interview was filmed in my office in the MRC-LMB and was aired on Cambridge TV in the News programme on the 6th April 2016. |
Year(s) Of Engagement Activity | 2016 |
Description | MRC-LMB annual open day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Industry/Business |
Results and Impact | The LMB holds an annual open day for the general public to showcase and communicate the ongoing research in the institute. In 2017, the open day was held on Saturday 17 June. |
Year(s) Of Engagement Activity | 2016,2017 |
URL | https://www2.mrc-lmb.cam.ac.uk/news-and-events/public-engagement/open-day/ |
Description | Phone interview with Nicole Davis from the Guardian |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | I was interviewed for and quoted in the article entitled "Zika structure discovered, raising hopes for new ways to combat virus" by Nicola Davis at The Guardian Newspaper highlighting a recent article contributed by another research group on the near-atomic structure of Zika virus in Science Magazine. This article was related to this project (but was not direct outcome of it). The article was published on the 31st March 2016. |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.theguardian.com/world/2016/mar/31/zika-structure-discovered-raising-hopes-for-new-ways-t... |
Description | Presentation and hand-on activities for Science Week to the students of St. Alban's Catholic Primary School, Cambridge, 19th March 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Presentation and hand-on activities on viruses, DNA and the scale of life for Science Week to the students of St. Alban's Catholic Primary School, Cambridge, 19th March 2018. This activity reached 60 pupils, aged 8-10 (Years 4 and 5). It included a presentation and hands-on activities including building a LEGO models of DNA and using an interactive computer program to explore and compare the scales of important components of life's building blocks (including DNA and viruses). |
Year(s) Of Engagement Activity | 2018 |
Description | Seminar for Non-Scientific Staff, MRC Laboratory of Molecular Biology, 27th November 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | This was a 20-min talk aimed at an audience with no scientific background at all, about the role of viruses in human health and disease. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.youtube.com/watch?v=zzGJNl6ZTIk&feature=youtu.be |