8TCO

HCMV Trimer in complex with CS2it1p2_F7K Fab and CS4tt1p1_E3K Fab

Summary for 8TCO

• Entry DOI: 10.2210/pdb8tco/pdb
• EMDB information: 41156 41157 41158 41160 41161
• Descriptor: Envelope glycoprotein H, 2-acetamido-2-deoxy-beta-D-glucopyranose, Envelope glycoprotein L, ... (10 entities in total)
• Functional Keywords: virus, glycoprotein, antibody, viral protein-immune system complex, viral protein/immune system
• Biological source: Human betaherpesvirus 5; More
• Total number of polymer chains: 7
• Total formula weight: 269731.10

Authors

Goldsmith, J.A.,McLellan, J.S. (deposition date: 2023-07-02, release date: 2023-08-09, Last modification date: 2024-10-23)

Primary citation

Zehner, M.,Alt, M.,Ashurov, A.,Goldsmith, J.A.,Spies, R.,Weiler, N.,Lerma, J.,Gieselmann, L.,Stohr, D.,Gruell, H.,Schultz, E.P.,Kreer, C.,Schlachter, L.,Janicki, H.,Laib Sampaio, K.,Stegmann, C.,Nemetchek, M.D.,Dahling, S.,Ullrich, L.,Dittmer, U.,Witzke, O.,Koch, M.,Ryckman, B.J.,Lotfi, R.,McLellan, J.S.,Krawczyk, A.,Sinzger, C.,Klein, F.
Single-cell analysis of memory B cells from top neutralizers reveals multiple sites of vulnerability within HCMV Trimer and Pentamer.
Immunity, 56:2602-2620.e10, 2023

PubMed Abstract: Human cytomegalovirus (HCMV) can cause severe diseases in fetuses, newborns, and immunocompromised individuals. Currently, no vaccines are approved, and treatment options are limited. Here, we analyzed the human B cell response of four HCMV top neutralizers from a cohort of 9,000 individuals. By single-cell analyses of memory B cells targeting the pentameric and trimeric HCMV surface complexes, we identified vulnerable sites on the shared gH/gL subunits as well as complex-specific subunits UL and gO. Using high-resolution cryogenic electron microscopy, we revealed the structural basis of the neutralization mechanisms of antibodies targeting various binding sites. Moreover, we identified highly potent antibodies that neutralized a broad spectrum of HCMV strains, including primary clinical isolates, that outperform known antibodies used in clinical trials. Our study provides a deep understanding of the mechanisms of HCMV neutralization and identifies promising antibody candidates to prevent and treat HCMV infection.

PubMed: 37967532
DOI: 10.1016/j.immuni.2023.10.009

Experimental method

ELECTRON MICROSCOPY (2.8 Å)