title: Cross-neutralization of influenza A viruses mediated by a single antibody loop.
abstract: Immune recognition of protein antigens relies on the combined interaction of multiple antibody loops, which provide a fairly large footprint and constrain the size and shape of protein surfaces that can be targeted. Single protein loops can mediate extremely high-affinity binding, but it is unclear whether such a mechanism is available to antibodies. Here we report the isolation and characterization of an antibody called C05, which neutralizes strains from multiple subtypes of influenza A virus, including H1, H2 and H3. X-ray and electron microscopy structures show that C05 recognizes conserved elements of the receptor-binding site on the haemagglutinin surface glycoprotein. Recognition of the haemagglutinin receptor-binding site is dominated by a single heavy-chain complementarity-determining region 3 loop, with minor contacts from heavy-chain complementarity-determining region 1, and is sufficient to achieve nanomolar binding with a minimal footprint. Thus, binding predominantly with a single loop can allow antibodies to target small, conserved functional sites on otherwise hypervariable antigens.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Damian C
authors.initials: DC
authors.lastname: Ekiert
authors.forename: Arun K
authors.initials: AK
authors.lastname: Kashyap
authors.forename: John
authors.initials: J
authors.lastname: Steel
authors.forename: Adam
authors.initials: A
authors.lastname: Rubrum
authors.forename: Gira
authors.initials: G
authors.lastname: Bhabha
authors.forename: Reza
authors.initials: R
authors.lastname: Khayat
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dillon
authors.forename: Ryann E
authors.initials: RE
authors.lastname: O'Neil
authors.forename: Aleksandr M
authors.initials: AM
authors.lastname: Faynboym
authors.forename: Michael
authors.initials: M
authors.lastname: Horowitz
authors.forename: Lawrence
authors.initials: L
authors.lastname: Horowitz
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Ward
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
authors.forename: Richard
authors.initials: R
authors.lastname: Webby
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lerner
authors.forename: Ramesh R
authors.initials: RR
authors.lastname: Bhatt
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D000914:Antibodies, Viral / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D000918:Antibody Specificity / Q000235:genetics / Q000276:immunology*; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology; D001665:Binding Sites; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D017124:Conserved Sequence; D003429:Cross Reactions / Q000235:genetics / Q000276:immunology; D018360:Crystallography, X-Ray; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000737:chemistry / Q000276:immunology; D009980:Influenza A virus / Q000737:chemistry / Q000145:classification* / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D011487:Protein Conformation
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D022801:Complementarity Determining Regions; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines