Distinct conformational states of HSV-2 gH/gL captured by cryoEM reveal structural principles governing fusion activation
Abstract
Orthoherpesviridae infect most humans for life and cause myriad diseases. These viruses distribute cell-entry functions among receptor-binding proteins such as gD, the conserved membrane fusogen gB, and the gH/gL heterodimer, which couples receptor engagement to gB activation. Here, we report cryoEM structures of HSV-2 gH/gL, including complexes with four antibody fragments, in distinct conformational states. Structural analysis suggests that these structures represent pre-activation and intermediate states rather than a post-activation state. Antibody binding appears to shift the gH/gL conformational equilibrium of gH/gL, either stabilizing the pre-activation state or promoting refolding into intermediate or post-activation-like states. Two regions – the N terminus and a domain H2 switch – adopt distinct conformations and may transmit the activating signal from gD to gB. We propose that receptor-bound gD displaces the gH N terminus, initiating allosteric rearrangements that culminate in switch refolding and may help release prefusion gB from an autoinhibited gH/gL-gB complex. Switch conservation suggests that this activation mechanism may be shared across Orthoherpesviridae . These findings uncover structural principles governing gH/gL-mediated activation of membrane fusion.
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BibTeX
@article{pino2026distinct,
title = {{Distinct conformational states of HSV-2 gH/gL captured by cryoEM reveal structural principles governing fusion activation}},
author = {Gonzalo L. González-Del Pino and Richard M. Walsh and Chanyoung Lee and Hunter C. Russell and Doina Atanasiu and Tina M. Cairns and Wan Ting Saw and Gary H. Cohen and Ekaterina E. Heldwein},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78793-2},
url = {https://www.nature.com/articles/s41467-026-78793-2},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Distinct conformational states of HSV-2 gH/gL captured by cryoEM reveal structural principles governing fusion activation
AU - Gonzalo L. González-Del Pino
AU - Richard M. Walsh
AU - Chanyoung Lee
AU - Hunter C. Russell
AU - Doina Atanasiu
AU - Tina M. Cairns
AU - Wan Ting Saw
AU - Gary H. Cohen
AU - Ekaterina E. Heldwein
PY - 2026
DA - 2026/10/27
JO - Nature Communications
DO - 10.1038/s41467-026-78793-2
UR - https://www.nature.com/articles/s41467-026-78793-2
AB - Orthoherpesviridae infect most humans for life and cause myriad diseases. These viruses distribute cell-entry functions among receptor-binding proteins such as gD, the conserved membrane fusogen gB, and the gH/gL heterodimer, which couples receptor engagement to gB activation. Here, we report cryoEM structures of HSV-2 gH/gL, including complexes with four antibody fragments, in distinct conformational states. Structural analysis suggests that these structures represent pre-activation and intermediate states rather than a post-activation state. Antibody binding appears to shift the gH/gL conformational equilibrium of gH/gL, either stabilizing the pre-activation state or promoting refolding into intermediate or post-activation-like states. Two regions – the N terminus and a domain H2 switch – adopt distinct conformations and may transmit the activating signal from gD to gB. We propose that receptor-bound gD displaces the gH N terminus, initiating allosteric rearrangements that culminate in switch refolding and may help release prefusion gB from an autoinhibited gH/gL-gB complex. Switch conservation suggests that this activation mechanism may be shared across Orthoherpesviridae . These findings uncover structural principles governing gH/gL-mediated activation of membrane fusion.
SN - 2041-1723
ER -