title: Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody.
abstract: The prefusion state of respiratory syncytial virus (RSV) fusion (F) glycoprotein is the target of most RSV-neutralizing activity in human sera, but its metastability has hindered characterization. To overcome this obstacle, we identified prefusion-specific antibodies that were substantially more potent than the prophylactic antibody palivizumab. The cocrystal structure for one of these antibodies, D25, in complex with the F glycoprotein revealed D25 to lock F in its prefusion state by binding to a quaternary epitope at the trimer apex. Electron microscopy showed that two other antibodies, AM22 and 5C4, also bound to the newly identified site of vulnerability, which we named antigenic site Ø. These studies should enable design of improved vaccine antigens and define new targets for passive prevention of RSV-induced disease.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. mclellanja@niaid.nih.gov
authors.forename: Jason S
authors.initials: JS
authors.lastname: McLellan
authors.forename: Man
authors.initials: M
authors.lastname: Chen
authors.forename: Sherman
authors.initials: S
authors.lastname: Leung
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Graepel
authors.forename: Xiulian
authors.initials: X
authors.lastname: Du
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.forename: Tongqing
authors.initials: T
authors.lastname: Zhou
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baxa
authors.forename: Etsuko
authors.initials: E
authors.lastname: Yasuda
authors.forename: Tim
authors.initials: T
authors.lastname: Beaumont
authors.forename: Azad
authors.initials: A
authors.lastname: Kumar
authors.forename: Kayvon
authors.initials: K
authors.lastname: Modjarrad
authors.forename: Zizheng
authors.initials: Z
authors.lastname: Zheng
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Ningshao
authors.initials: N
authors.lastname: Xia
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D018360:Crystallography, X-Ray; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D000069455:Palivizumab; D011487:Protein Conformation; D055503:Protein Multimerization; D022261:Respiratory Syncytial Virus Vaccines / Q000737:chemistry / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology* / Q000502:physiology; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000276:immunology*; D053586:Virus Internalization
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D006023:Glycoproteins; D022261:Respiratory Syncytial Virus Vaccines; D014760:Viral Fusion Proteins; D000069455:Palivizumab