7B7N

Human herpesvirus-8 gH/gL in complex with EphA2

Summary for 7B7N

• Entry DOI: 10.2210/pdb7b7n/pdb
• Descriptor: Ephrin type-A receptor 2, Envelope glycoprotein H, Envelope glycoprotein L, ... (8 entities in total)
• Functional Keywords: complex, receptor, viral protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 121376.79

Authors

Pederzoli, R.,Guardado-Calvo, P.,Rey, F.A.,Backovic, M. (deposition date: 2020-12-11, release date: 2020-12-30, Last modification date: 2024-01-31)

Primary citation

Light, T.P.,Brun, D.,Guardado-Calvo, P.,Pederzoli, R.,Haouz, A.,Neipel, F.,Rey, F.A.,Hristova, K.,Backovic, M.
Human herpesvirus 8 molecular mimicry of ephrin ligands facilitates cell entry and triggers EphA2 signaling.
Plos Biol., 19:e3001392-e3001392, 2021

PubMed Abstract: Human herpesvirus 8 (HHV-8) is an oncogenic virus that enters cells by fusion of the viral and endosomal cellular membranes in a process mediated by viral surface glycoproteins. One of the cellular receptors hijacked by HHV-8 to gain access to cells is the EphA2 tyrosine kinase receptor, and the mechanistic basis of EphA2-mediated viral entry remains unclear. Using X-ray structure analysis, targeted mutagenesis, and binding studies, we here show that the HHV-8 envelope glycoprotein complex H and L (gH/gL) binds with subnanomolar affinity to EphA2 via molecular mimicry of the receptor's cellular ligands, ephrins (Eph family receptor interacting proteins), revealing a pivotal role for the conserved gH residue E52 and the amino-terminal peptide of gL. Using FSI-FRET and cell contraction assays, we further demonstrate that the gH/gL complex also functionally mimics ephrin ligand by inducing EphA2 receptor association via its dimerization interface, thus triggering receptor signaling for cytoskeleton remodeling. These results now provide novel insight into the entry mechanism of HHV-8, opening avenues for the search of therapeutic agents that could interfere with HHV-8-related diseases.

PubMed: 34499637
DOI: 10.1371/journal.pbio.3001392

Experimental method

X-RAY DIFFRACTION (2.69 Å)