9ISH

Crystal structure of nanobody 32 in complex with HSV-2 gD

Summary for 9ISH

• Entry DOI: 10.2210/pdb9ish/pdb
• Descriptor: Glycoprotein D, Nanobody 32, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: herpes simplex virus, nanobody, antiviral protein
• Biological source: Human alphaherpesvirus 2; More
• Total number of polymer chains: 4
• Total formula weight: 91070.75

Authors

Hu, J.,Jin, T.C. (deposition date: 2024-07-17, release date: 2025-05-28)

Primary citation

Hu, J.,Tan, H.,Wang, M.,Deng, S.,Liu, M.,Zheng, P.,Wang, A.,Guo, M.,Wang, J.,Li, J.,Qiu, H.,Yao, C.,Zhu, Z.,Hasi, C.,Pan, D.,He, H.,Huang, C.,Shang, Y.,Zhu, S.,Jin, T.
A potent protective bispecific nanobody targeting Herpes simplex virus gD reveals vulnerable epitope for neutralizing.
Nat Commun, 16:4196-4196, 2025

PubMed Abstract: Herpes simplex virus (HSV) causes significant health burden worldwide. Currently used antiviral drugs are effective but resistance can occur. Here, we report two high-affinity neutralizing nanobodies, namely Nb14 and Nb32, that target non-overlapping epitopes in HSV gD. Nb14 binds a neutralization epitope located in the N-A' interloop, which prevents the interaction between gD and gH/gL during the second step of conformational changes during membrane fusion after virus attachment. The bispecific nanobody dimer (Nb14-32-Fc) exhibits high potency in vitro and in vivo. Mechanistically, Nb14-32-Fc neutralizes HSVs at both the pre-and post-attachment stages and prevents cell-to-cell spread in vitro. Administration of Nb14-32-Fc at low dosage of 1 mg/kg provides 100% protection in an HSV-1 infection male mouse model and an HSV-2 infection female mouse model. Our results demonstrate that Nb14-32-Fc could serve as a promising drug candidate for treatment of HSV infection, especially in the cases of antiviral drug resistance and severe herpes encephalitis.

PubMed: 40328740
DOI: 10.1038/s41467-025-58669-7

Experimental method

X-RAY DIFFRACTION (2.88 Å)