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Structural Basis of Pan-Ebolavirus Neutralization by an Antibody Targeting the Glycoprotein Fusion Loop.

08:00 EDT 4th September 2018 | BioPortfolio

Summary of "Structural Basis of Pan-Ebolavirus Neutralization by an Antibody Targeting the Glycoprotein Fusion Loop."

Monoclonal antibodies (mAbs) with pan-ebolavirus cross-reactivity are highly desirable, but development of such mAbs is limited by a lack of a molecular understanding of cross-reactive epitopes. The antibody ADI-15878 was previously identified from a human survivor of Ebola virus Makona variant (EBOV/Mak) infection. This mAb demonstrated potent neutralizing activity against all known ebolaviruses and provided protection in rodent and ferret models against three ebolavirus species. Here, we describe the unliganded crystal structure of ADI-15878 as well as the cryo-EM structures of ADI-15878 in complex with the EBOV/Mak and Bundibugyo virus (BDBV) glycoproteins (GPs). ADI-15878 binds through an induced-fit mechanism by targeting highly conserved residues in the internal fusion loop (IFL), bridging across GP protomers via the heptad repeat 1 (HR1) region. Our structures provide a more complete description of the ebolavirus immunogenic landscape, as well as a molecular basis for how rare but potent antibodies target conserved filoviral fusion machinery.

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Journal Details

This article was published in the following journal.

Name: Cell reports
ISSN: 2211-1247
Pages: 2723-2732.e4

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Medical and Biotech [MESH] Definitions

A class I viral fusion protein that forms the characteristic spikes, or peplomers, found on the viral surface that mediate virus attachment, fusion, and entry into the host cell. During virus maturation, it is cleaved into two subunits: S1, which binds to receptors in the host cell, and S2, which mediates membrane fusion.

A genus in the family FILOVIRIDAE consisting of several distinct species of Ebolavirus, each containing separate strains. These viruses cause outbreaks of a contagious, hemorrhagic disease (HEMORRHAGIC FEVER, EBOLA) in humans, usually with high mortality.

The GENETIC RECOMBINATION of the parts of two or more GENES resulting in a gene with different or additional regulatory regions, or a new chimeric gene product. ONCOGENE FUSION includes an ONCOGENE as at least one of the fusion partners and such gene fusions are often detected in neoplastic cells and are transcribed into ONCOGENE FUSION PROTEINS. ARTIFICIAL GENE FUSION is carried out in vitro by RECOMBINANT DNA technology.

A transmembrane glycoprotein subunit that can dimerize with a variety of light chain subunits such as SLC7A5; SLC7A6, and 4F2 LIGHT CHAINS. This protein subunit serves a diverse array of functions including amino acid transport and cell fusion. Its function is altered depending which of the light chain subunits it interacts with.

The phenomenon of immense variability characteristic of ANTIBODIES. It enables the IMMUNE SYSTEM to react specifically against the essentially unlimited kinds of ANTIGENS it encounters. Antibody diversity is accounted for by three main theories: (1) the Germ Line Theory, which holds that each antibody-producing cell has genes coding for all possible antibody specificities, but expresses only the one stimulated by antigen; (2) the Somatic Mutation Theory, which holds that antibody-producing cells contain only a few genes, which produce antibody diversity by mutation; and (3) the Gene Rearrangement Theory, which holds that antibody diversity is generated by the rearrangement of IMMUNOGLOBULIN VARIABLE REGION gene segments during the differentiation of the ANTIBODY-PRODUCING CELLS.

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