title: Structure of HCMV glycoprotein B in the postfusion conformation bound to a neutralizing human antibody.
abstract: Human cytomegalovirus (HCMV) poses a significant threat to immunocompromised individuals and neonates infected in utero. Glycoprotein B (gB), the herpesvirus fusion protein, is a target for neutralizing antibodies and a vaccine candidate due to its indispensable role in infection. Here we show the crystal structure of the HCMV gB ectodomain bound to the Fab fragment of 1G2, a neutralizing human monoclonal antibody isolated from a seropositive subject. The gB/1G2 interaction is dominated by aromatic residues in the 1G2 heavy chain CDR3 protruding into a hydrophobic cleft in the gB antigenic domain 5 (AD-5). Structural analysis and comparison with HSV gB suggest the location of additional neutralizing antibody binding sites on HCMV gB. Finally, immunoprecipitation experiments reveal that 1G2 can bind to HCMV virion gB suggesting that its epitope is exposed and accessible on the virus surface. Our data will support the development of vaccines and therapeutic antibodies against HCMV infection.
authors.affiliation: GSK Vaccines, 45 Sidney Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Sumana
authors.initials: S
authors.lastname: Chandramouli
authors.affiliation: GSK Vaccines, 45 Sidney Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ciferri
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, California 94608, USA.
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Nikitin
authors.affiliation: GSK Vaccines, Via Fiorentina 1, Siena 53100, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Caló
authors.affiliation: GSK Vaccines, 45 Sidney Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gerrein
authors.affiliation: GSK Vaccines, 45 Sidney Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Balabanis
authors.affiliation: GSK Vaccines, 45 Sidney Street, Cambridge, Massachusetts 02139, USA.
authors.forename: James
authors.initials: J
authors.lastname: Monroe
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, California 94608, USA.
authors.forename: Christy
authors.initials: C
authors.lastname: Hebner
authors.affiliation: GSK Vaccines, 45 Sidney Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Anders E
authors.initials: AE
authors.lastname: Lilja
authors.affiliation: Novartis Influenza Vaccines, 45 Sidney Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Ethan C
authors.initials: EC
authors.lastname: Settembre
authors.affiliation: GSK Vaccines, 45 Sidney Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfi
mesh_terms: D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D000914:Antibodies, Viral / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D000956:Antigens, Viral / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D003460:Crystallization; D018360:Crystallography, X-Ray; D003587:Cytomegalovirus / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D047468:Immunoprecipitation; D008854:Microscopy, Electron; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D007140:Immunoglobulin Fab Fragments; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; C040495:glycoprotein B, Simplexvirus