8U9Y

CryoEM structure of neutralizing antibody HC84.26 in complex with Hepatitis C virus envelope glycoprotein E2_New interface

Summary for 8U9Y

• Entry DOI: 10.2210/pdb8u9y/pdb
• Related: 8TGV 8TGZ
• EMDB information: 41245 41247 42041
• Descriptor: Envelope glycoprotein E2, HC84.26 heavy chain, HC84.26 light chain, ... (7 entities in total)
• Functional Keywords: hcv, e2, fab, antiviral, complex, viral protein-immune system complex, viral protein/immune system
• Biological source: Hepacivirus; More
• Total number of polymer chains: 5
• Total formula weight: 140389.38

Authors

Shahid, S.,Liqun, J.,Liu, Y.,Hasan, S.S.,Mariuzza, R.A. (deposition date: 2023-09-20, release date: 2024-09-25, Last modification date: 2025-07-09)

Primary citation

Shahid, S.,Karade, S.S.,Hasan, S.S.,Yin, R.,Jiang, L.,Liu, Y.,Felbinger, N.,Kulakova, L.,Toth, E.A.,Keck, Z.Y.,Foung, S.K.H.,Fuerst, T.R.,Pierce, B.G.,Mariuzza, R.A.
Cryo-EM structures of HCV E2 glycoprotein bound to neutralizing and non-neutralizing antibodies determined using bivalent Fabs as fiducial markers.
Commun Biol, 8:825-825, 2025

PubMed Abstract: Global elimination of hepatitis C virus (HCV) will require an effective cross-genotype vaccine. The HCV E2 envelope glycoprotein is the main target of neutralizing antibodies but also contains epitopes that elicit non-neutralizing antibodies which may provide protection through Fc effector functions rather than direct neutralization. We determined cryo-EM structures of a broadly neutralizing antibody, a moderately neutralizing antibody, and a non-neutralizing antibody bound to E2 to resolutions of 3.8, 3.3, and 3.7 Å, respectively. Whereas the broadly neutralizing antibody targeted the front layer of E2 and the non-neutralizing antibody targeted the back layer, the moderately neutralizing antibody straddled both front and back layers, and thereby defined a new neutralizing epitope on E2. The small size of complexes between conventional (monovalent) Fabs and E2 (~110 kDa) presented a challenge for cryo-EM. Accordingly, we engineered bivalent versions of E2-specific Fabs that doubled the size of Fab-E2 complexes and conferred highly identifiable shapes to the complexes that facilitated particle selection and orientation for image processing. This study validates bivalent Fabs as new fiducial markers for cryo-EM analysis of small proteins such as HCV E2 and identifies a new target epitope for vaccine development.

PubMed: 40442315
DOI: 10.1038/s42003-025-08239-w

Experimental method

ELECTRON MICROSCOPY (3.7 Å)