9MSK

Structure of hepatitis C virus envelope glycoprotein E2 core from isolate H77 bound to neutralizing antibody RM3-26

Summary for 9MSK

• Entry DOI: 10.2210/pdb9msk/pdb
• Descriptor: RM3-26 fab heavy chain, RM3-26 fab light chain, Envelope glycoprotein E2, ... (5 entities in total)
• Functional Keywords: immunity proteins, viral protein-immune system complex, viral protein/immune system
• Biological source: Macaca mulatta (Rhesus monkey); More
• Total number of polymer chains: 3
• Total formula weight: 67702.62

Authors

Nguyen, T.K.Y.,Wilson, I.A. (deposition date: 2025-01-09, release date: 2026-07-01)

Primary citation

Chen, F.,Nguyen, Y.T.K.,Lee, Y.Z.,Giang, E.,Lau, S.C.,Koide, Y.,Hung, S.H.,Ueno, L.,He, L.,Fuerst, T.R.,Lauer, G.M.,Stanfield, R.L.,Zhu, J.,Wilson, I.A.,Law, M.
The conserved bridging domain on HCV E1E2 glycoprotein complex is targeted by neutralizing antibodies from diverse lineages.
Biorxiv, 2025

PubMed Abstract: The induction of potent and cross-reactive neutralizing antibody (nAb) responses remains a challenge in vaccine development against antigenically diverse viruses such as hepatitis C virus (HCV). The HCV E1E2 glycoprotein complex contains two major neutralizing sites: the neutralizing face (NF) and the less explored bridging domain (BD). Here, we characterized 25 BD-targeting nAbs isolated from infection or immunization. These antibodies arise from diverse B cell lineages but share convergent CDRH3 features. Epitope mapping by alanine scanning and negative-stain electron microscopy revealed overlapping epitopes on BD spanning antigenic regions AR4 and AR5, with variable back layer engagement. The crystal structure of a non-human primate BD nAb RM3-26 in complex with E2 uncovered a back layer-directed recognition mode analogous to that of the human nAb hcab40. Together, BD- and NF-directed nAbs exhibited additivity in their neutralization, highlighting BD as a conserved site of vulnerability on HCV and a valuable target for rational vaccine design.

PubMed: 41280117
DOI: 10.1101/2025.11.05.686883

Experimental method

X-RAY DIFFRACTION (2.23 Å)