Figure 1. Mutations in the SARS-CoV-2 spike glycoprotein. NTD, N-terminal domain; RBD, receptor binding domain; FCS, furin cleavage site; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2; TM, transmembrane anchor; IC, intracellular tail. The Delta symbol indicates deletion. Mutations as defined by the Centers for Disease Control and Prevention.

Figure 1. Mutations in the SARS-CoV-2 spike glycoprotein. NTD, N-terminal domain; RBD, receptor binding domain; FCS, furin cleavage site; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2; TM, transmembrane anchor; IC, intracellular tail. The Delta symbol indicates deletion. Mutations as defined by the Centers for Disease Control and Prevention.

Figure 2. The N-terminal domain (NTD) of the SARS-CoV-2 spike glycoprotein exhibits a high level of flexibility. The cryo-EM structure of the prefusion spike protein is colored by B-factor; the thickness of the wire corresponds to structural variability.

Figure 2. The N-terminal domain (NTD) of the SARS-CoV-2 spike glycoprotein exhibits a high level of flexibility. The cryo-EM structure of the prefusion spike protein is colored by B-factor; the thickness of the wire corresponds to structural variability.

Figure 3. Mutations in the N-terminal domain (NTD) cluster in a manner that likely modulates binding interactions. The spike glycoprotein is shown in gray with mutations present in variants of concern (VOC) shown in red, NTD VOC mutations in red, RBD VOC mutations in green, interchain contact VOC mutations in magenta, furin cleavage site mutations shown in yellow, ACE2 shown in cyan, CEACAM1 shown in orange.

Figure 3. Mutations in the N-terminal domain (NTD) cluster in a manner that likely modulates binding interactions. The spike glycoprotein is shown in gray with mutations present in variants of concern (VOC) shown in red, NTD VOC mutations in red, RBD VOC mutations in green, interchain contact VOC mutations in magenta, furin cleavage site mutations shown in yellow, ACE2 shown in cyan, CEACAM1 shown in orange.

Figure 4. SARS-CoV-2 variants of concern (VOC) acquire mutations in the N-terminal domain (NTD) at the sites of the highest flexibility. The cryo-EM structure of the prefusion spike glycoprotein is shown. Top panel, the NTD is shown in gray; mutations in variants of concern are shown in red; bottom panel, the NTD is colored by B-factor, indicating structural variability.

Figure 4. SARS-CoV-2 variants of concern (VOC) acquire mutations in the N-terminal domain (NTD) at the sites of the highest flexibility. The cryo-EM structure of the prefusion spike glycoprotein is shown. Top panel, the NTD is shown in gray; mutations in variants of concern are shown in red; bottom panel, the NTD is colored by B-factor, indicating structural variability.

Figure 5. Structural model of LRRC15 complexed to the NTD of the SARS-CoV-2 spike glycoprotein. The cryo-EM structure of the spike protein is shown in gray complexed to LRRC15, shown in gold. Spike mutations from the omicron variant are shown in blue.

Figure 5. Structural model of LRRC15 complexed to the NTD of the SARS-CoV-2 spike glycoprotein. The cryo-EM structure of the spike protein is shown in gray complexed to LRRC15, shown in gold. Spike mutations from the omicron variant are shown in blue.

Figure 6. Structural model of Neuropilin-1 complexed to the NTD of the SARS-CoV-2 spike glycoprotein monomer. The cryo-EM structure of the spike protein monomer is shown in gray complex to neuropilin-1, shown in magenta. Spike mutations from the omicron variant are shown in blue.

Figure 6. Structural model of Neuropilin-1 complexed to the NTD of the SARS-CoV-2 spike glycoprotein monomer. The cryo-EM structure of the spike protein monomer is shown in gray complex to neuropilin-1, shown in magenta. Spike mutations from the omicron variant are shown in blue.

Table 1. Summary of potential coreceptor ligands of the SARS-CoV-2 spike protein.

Table 1. Summary of potential coreceptor ligands of the SARS-CoV-2 spike protein.

LigandDescriptionProposed Virological FunctionReferencesSialic acidSugar chain with nine-carbon backbone found on the surfaces of all vertebrate cells.
Implicated in various functions and diseases.S1-NTD may bind sialic acids in a sialosides-binding pocket that resembles that of the MERS-CoV S1-NTD.
Sialic acid may act as a coreceptor to help S1 reach ACE2 via viral surfing, or it may inhibit ACE2-S1 binding.[4,11,17,46]Monosialylated gangliosides (GM1, GM2, GM3)Sialic acid-containing glycosphingolipids widely expressed in the nervous system.
As part of the plasma membrane’s outer leaflet, these sugar chains are key to cell-cell recognition, adhesion, and signal transduction.Negatively charged flat surface may attract the electropositive tip of virus envelope proteins.
Association with cholesterol to form lipid rafts could enhance fusion.
Membrane chaperone properties could enhance activation of viral proteins.[19,21,47]Heparan sulfate proteoglycans (HSPGs)Glycoprotein with attached heparan sulfate polysaccharide chains.
Found as a cellular receptor in almost all mammalian cells with functions related to development, inflammation, coagulation, angiogenesis, and viral entry.Binding between HSPGs/HS and a polyanionic path along the S1-RBD, NTD, and FCS may enhance the open conformation of the RBD, supporting RBD-ACE2 binding.[23,24,25,26]Leucine-rich repeat-containing protein 15 (LRRC15)Protein family with unrelated functions and characteristic α/β-horseshoe shape with leucine-rich tandem repeats.
Functions of LRRC15 include innate immunity, down regulation of protein localization to the plasma membrane, and nervous system development.LRRC15 may sequester and immobilize SARS-CoV-2 virions.
Upregulated by proinflammatory cytokines, LRRC15 could suppress lung fibrosis during virus-induced inflammation.
Demonstrated affinity for S1-NTD.[31,32,33,34,35,37]Neuropilin-1 (NRP-1)Glycoprotein receptor found on cell membranes of neurons with functions related to angiogenesis, neuronal development, and immune response regulation.Potentially enables SARS-CoV-2 virions to enter the nervous system through respiratory and olfactory epithelia.
Known to bind furin-cleaved substrates.[38,39,40]