9Z3Q

Cryo-EM structure of KSHV glycoprotein gHgL in complex with MLKH3 and MLKH10 FABs

Summary for 9Z3Q

• Entry DOI: 10.2210/pdb9z3q/pdb
• EMDB information: 73789
• Descriptor: MLKH10 Light chain FV, MLKH10 Heavy chain FV, MLKH3 Light chain FV, ... (6 entities in total)
• Functional Keywords: kshv, glycoprotein, antibody, immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 6
• Total formula weight: 149932.70

Authors

Lang, K.,Aldridge, N.,Pancera, M. (deposition date: 2025-11-07, release date: 2025-12-10, Last modification date: 2026-01-21)

Primary citation

Wan, Y.H.,Pernikoff, S.,Aldridge, N.T.,Lang, K.,Dudley, H.M.,Scharffenberger, S.C.,Kher, G.,Phipps, W.,Pancera, M.,Boonyaratanakornkit, J.,McGuire, A.T.
Monoclonal neutralizing antibodies elicited by infection with Kaposi sarcoma-associated herpesvirus reveal critical sites of vulnerability on gH/gL.
Plos Pathog., 22:e1013772-e1013772, 2026

PubMed Abstract: Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that causes Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. A vaccine that prevents KSHV infection or serves in the treatment of KSHV-related diseases represents a critical unmet need, however, the types of immune responses a vaccine should elicit have not been well defined. The gH/gL glycoprotein complex is an important target of KSHV-neutralizing antibodies, but the epitope specificities targeted by these antibodies remain unknown. Here, we isolated 12 gH/gL-specific monoclonal antibodies (mAbs) from KSHV-infected donors and performed structure/function analyses. These mAbs bind recombinant gH/gL with nanomolar affinities and epitope binning analyses revealed that the mAbs bind to 5 epitope clusters on gH/gL. Seven mAbs were able to neutralize KSHV infection of epithelial cell lines. Two potent neutralizing mAbs mapped to the EphA2 binding site as determined by inhibition of the receptor-ligand interaction and negative stain electron microscopy (nsEM) of the mAb/gH/gL complex. The epitopes of other neutralizing mAbs targeting novel sites of vulnerability were determined by a combination of cryogenic electron microscopy and nsEM. Together, these mAbs help to define the relevant epitope targets for KSHV vaccine design, have utility in understanding the role of antibodies in preventing KSHV infection, enable the development of immunotherapy approaches, and provide valuable tools to understand the molecular details of the KSHV entry process.

PubMed: 41499715
DOI: 10.1371/journal.ppat.1013772

Experimental method

ELECTRON MICROSCOPY (3.51 Å)