Recently, prof. George Fu Gao’s group described the molecular mechanism of KSHV gHgL and EBV gHgL binding to EphA2 receptor. The article entitled “Molecular basis of EphA2 recognition by gHgL from gammaherpesviruses” was published in Nature Communications on November 24, 2020.

The human γ-herpesviruses Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are associated with many human malignancies. Viral glycoprotein H (gH) and glycoprotein L (gL) are crucial for the cell tropism by binding to specific receptors. Recently, EphA2 was identified as the specific entry receptor for both KSHV and EBV. However, it is still unclear for the molecular mechanism of EphA2 recognition by gHgL.

They characterized the crystal structures of KSHV gHgL or EBV gHgL in complex with the ligand binding domain (LBD) of EphA2. Both KSHV and EBV gHgL bind to the channel and peripheral regions of LBD primarily using gL. Extensive interactions with more contacts contribute to the higher affinity of KSHV gHgL to LBD than that of EBV gHgL. These binding characteristics were verified using cell-based fusion assays with mutations in key EphA2 residues.