E2 is the main HCV receptor binding protein and the primary target for broadly neutralizing antibodies (bnAbs). The receptor binding domain (residues 384 to 645), also known as E2 core domain, is modified by up to 11 N-linked glycans and contains several variable regions that increase the genetic diversity of HCV for evasion of the immune system. Crystal structures of E2 from different HCV strains are all very similar, with the E2 core domain consisting of a central immunoglobulin (Ig)β-sandwich fold stabilized by eight disulfides and flanked by N-terminal hypervariable region 1, a front layer, and a C-terminal back layer (residues 597 to 645). The high density of the disulfide bonds contributes to the high thermal stability of E2, although the receptor binding site in recombinant E2 exhibits high conformational flexibility.