To date, there are several structural data of the SARS-CoV-2 protein in the prefusion conformation or bound to its primary receptor ACE-2 [11, 20]. However, ACE-2 is in lipid rafts and raft disruption induces a marked decrease of virus infection [15]. Thus, it is likely that the virus interacts with the raft surface through multivalent contacts involving both ACE-2 and gangliosides. The fact that the RBD and the ganglioside-binding domain belong to distinct parts of the trimeric spike is consistent with this notion. Such a complex network of virus-host cell membrane interactions is also consistent with previously characterized virus infection strategies. Indeed, the HIV-1 fusion process driven by gp120 and gp41 envelope proteins involves a receptor (CD4), a coreceptor (chiefly CCR5) and glycosphingolipid cofactors [39]. Like SARS-CoV-2, the pentameric capsid protein of SV40, and polyoma viruses display three distinct binding sites for gangliosides, which serve as critical receptors for these non-enveloped viruses in lipid raft domains [40].