4XI5

gHgL of varicella-zoster virus in complex with human neutralizing antibodies

Summary for 4XI5

• Entry DOI: 10.2210/pdb4xi5/pdb
• Related: 4XHJ
• Descriptor: Envelope glycoprotein H, Envelope glycoprotein L, Fab-94 light chain, ... (6 entities in total)
• Functional Keywords: complex, neutralization epitope, viral protein-immune system complex, viral protein/immune system
• Biological source: Human herpesvirus 3 strain Oka vaccine (HHV-3); More
• Cellular location: Virion membrane ; Single-pass type I membrane protein : Q775J3; Virion membrane ; Peripheral membrane protein ; Extracellular side : Q9J3N1
• Total number of polymer chains: 4
• Total formula weight: 162744.49

Authors

Xing, Y. (deposition date: 2015-01-06, release date: 2015-05-13, Last modification date: 2024-10-23)

Primary citation

Xing, Y.,Oliver, S.L.,Nguyen, T.,Ciferri, C.,Nandi, A.,Hickman, J.,Giovani, C.,Yang, E.,Palladino, G.,Grose, C.,Uematsu, Y.,Lilja, A.E.,Arvin, A.M.,Carfi, A.
A site of varicella-zoster virus vulnerability identified by structural studies of neutralizing antibodies bound to the glycoprotein complex gHgL.
Proc.Natl.Acad.Sci.USA, 112:6056-6061, 2015

PubMed Abstract: Varicella-zoster virus (VZV), of the family Alphaherpesvirinae, causes varicella in children and young adults, potentially leading to herpes zoster later in life on reactivation from latency. The conserved herpesvirus glycoprotein gB and the heterodimer gHgL mediate virion envelope fusion with cell membranes during virus entry. Naturally occurring neutralizing antibodies against herpesviruses target these entry proteins. To determine the molecular basis for VZV neutralization, crystal structures of gHgL were determined in complex with fragments of antigen binding (Fabs) from two human monoclonal antibodies, IgG-94 and IgG-RC, isolated from seropositive subjects. These structures reveal that the antibodies target the same site, composed of residues from both gH and gL, distinct from two other neutralizing epitopes identified by negative-stain electron microscopy and mutational analysis. Inhibition of gB/gHgL-mediated membrane fusion and structural comparisons with herpesvirus homologs suggest that the IgG-RC/94 epitope is in proximity to the site on VZV gHgL that activates gB. Immunization studies proved that the anti-gHgL IgG-RC/94 epitope is a critical target for antibodies that neutralize VZV. Thus, the gHgL/Fab structures delineate a site of herpesvirus vulnerability targeted by natural immunity.

PubMed: 25918416
DOI: 10.1073/pnas.1501176112

Experimental method

X-RAY DIFFRACTION (3.9 Å)