9OM5

Composite map of six VRC35 Fabs and three MEDI8852 Fabs bound to influenza H3N2 Victoria 2011 hemagglutinin

Summary for 9OM5

• Entry DOI: 10.2210/pdb9om5/pdb
• EMDB information: 70607
• Descriptor: Hemagglutinin, 2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose, ... (11 entities in total)
• Functional Keywords: broadly neutralizing antibody, cryo-em, hemagglutinin, high mannose, homotypic interactions, influenza a virus, multimeric recognition, n-linked glycan, antiviral protein, viral protein, viral protein-immune system complex, viral protein/immune system
• Biological source: Influenza A virus; More
• Total number of polymer chains: 24
• Total formula weight: 637227.66

Authors

Cheng, J.,Cale, E.M.,Longo, N.,Sutton, M.S.,Lei, H.,Huang, R.,Morton, A.J.,Lang, Z.C.,Morano, N.C.,Roark, R.S.,Becker, J.E.,Tsybovsky, Y.,Li, N.,Zhang, B.,Du, H.,Rubin, S.,Shapiro, L.,Pierson, T.C.,Doria-Rose, N.A.,Kwong, P.D.,Zhou, T. (deposition date: 2025-05-13, release date: 2026-05-27, Last modification date: 2026-09-09)

Primary citation

Cheng, J.,Cale, E.M.,Maghsoudi, A.,Sutton, M.S.,Longo, N.S.,Gillespie, R.A.,Wang, L.,Kosik, I.,Chong, S.,Yasuhara, A.,Bylund, T.,Schon, A.,Tripathi, P.,Tsybovsky, Y.,Lei, H.,Morano, N.C.,Lupatkin, A.B.,Morton, A.J.,Lang, Z.C.,Becker, J.E.,Frascilla, I.R.,Lee, M.,Li, N.,Liu, C.,Roark, R.S.,Shen, C.H.,Teng, I.T.,Van Wazer, D.J.,Wang, D.,Wu, L.,Ahlsen, G.,Castro, M.,Du, H.,Ernandes, M.J.,Li, T.,Lin, B.C.,Louder, M.K.,McKee, K.,Merriam, J.S.,O'Dell, S.,Ou, L.,Pletnev, S.,Prikryl, D.,Qiu, Q.,Rubin, S.,Sastry, M.,Schmidt, S.D.,Shajahan, A.,Shiakolas, A.R.,Srivatsan, S.,Zhang, B.,Zhou, Q.,Connors, M.,Gall, J.G.,Guo, Y.,Huang, R.K.,Huang, Y.,Koup, R.A.,Lei, Q.P.,Mascola, J.R.,Rawi, R.,Serebryannyy, L.,Shapiro, L.,Sheng, Z.,Ho, D.D.,Wilson, P.C.,Yewdell, J.W.,Pierson, T.C.,Kanekiyo, M.,Doria-Rose, N.A.,Kwong, P.D.,Zhou, T.
Canonical Antibodies Adopt Distinct Binding Modes to Recognize Viral Glycan Shields.
Adv Sci, :e77172-e77172, 2026

PubMed Abstract: Viral entry glycoproteins are often shielded from immune recognition by dense N-linked glycans that limit antibody access to protein epitopes. While glycan-reactive antibodies with unusual architectures have been described, how canonical Y-shaped antibodies engage these glycan-rich surfaces remains poorly defined. Here, we characterize two human antibodies, VRC35 and VRC36, isolated from an HIV-1-infected donor, that recognize diverse glycosylated viral glycoproteins. Cryo-electron microscopy structural analyses of these antibodies in complex with viral entry glycoproteins, including HIV-1 envelope, influenza hemagglutinin, SARS-CoV-2 spike, and the Lassa virus glycoprotein complex, reveal adaptive Fab stoichiometries ranging from single-Fab binding to dimeric and higher-order assemblies are mediated by intra- and inter-IgG interactions that depend on local glycan organization. Dense glycan clustering on HIV-1 and influenza glycoproteins supports multivalent Fab assemblies and correlates with neutralization activity, whereas sparse glycan environments on SARS-CoV-2 and Lassa virus favor weak or heterogeneous engagement without neutralization. Structural and mutational analyses further demonstrate that homotypic Fab-Fab interactions stabilize multivalent engagement and contribute to neutralizing activity. Together, these findings define a structural framework in which viral glycan organization constrains antibody valency and engagement, while somatic hypermutation contributes to the acquisition of homotypic Fab-Fab interactions that facilitate multivalent recognition of viral glycan shields.

PubMed: 42598737
DOI: 10.1002/advs.77172

Experimental method

ELECTRON MICROSCOPY (3.4 Å)