Paratope

• Article • • 15 June 2023 Mechanistic basis for potent neutralization of Sin Nombre hantavirus by a human monoclonal antibody • ORCID: orcid.org/0000-0002-5224-0036 • ORCID: orcid.org/0000-0002-6280-4405 • • ORCID: orcid.org/0000-0003-2896-7515 • ORCID: orcid.org/0000-0001-8658-4411 • • ORCID: orcid.org/0000-0002-0049-1079 • … • ORCID: orcid.org/0000-0002-8066-8785 Show authors Nature Microbiology ( 2023) Rodent-borne hantaviruses are prevalent worldwide and upon spillover to human populations, cause severe disease for which no specific treatment is available. A potent antibody response is key for recovery from hantavirus infection. Here we study a highly neutralizing human monoclonal antibody, termed SNV-42, which was derived from a memory B cell isolated from an individual with previous Sin Nombre virus (SNV) infection. Crystallographic analysis demonstrates that SNV-42 targets the Gn subcomponent of the tetrameric (Gn−Gc) 4 glycoprotein assembly that is relevant for viral entry. Integration of our 1.8 Å structure with the (Gn−Gc) 4 ultrastructure arrangement indicates that SNV-42 targets the membrane-distal region of the virus envelope. Comparison of the SNV-42 paratope encoding variable genes with inferred germline gene segments reveals high sequence conservation, suggesting that germline-encoded antibodies inhibit SNV. Furthermore, mechanistic assays reveal that SNV-42 interferes with both receptor recognition and fusion during host-cell entry. This work provides a m...

\( \newcommand\) • • • • • • A region at the tip of the antibody protein is very variable, allowing millions of antibodies with different antigen-binding sites to exist. Key Points • An antibody (Ab), also known as an immunoglobulin (Ig), is a large protein produced by B-cells that is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, called an antigen. • Each tip of the “Y” of an antibody contains a paratope that is specific for one particular epitope (analogous to a lock and key) on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell. • The general structure of all antibodies is very similar: The Ig monomer is a Y-shaped molecule that consists of four polypeptide chains: two identical heavy chains and two identical light chains connected by disulphide bonds. • Antibodies can occur in two physical forms, a soluble form that is secreted from the cell, and a membrane-bound form that is attached to the surface of a B-cell and is referred to as the B-cell receptor (BCR). Key Terms • Hypervariable region: In antibodies, hypervariable regions form the antigen-binding site and are found on both light and heavy chains. They also contribute to the specificity of each antibody. In a variable region, the 3 HV segments of each heavy or light chain fold together at the N-term...