Steric hindrance of antibody binding in an Omicron spike fusion intermediate

a, Surface representation of apo D614G SE-FIC, WT SE-FIC-76E1 and XBB.1.5 SE-FIC-76E1 structures. ACE2, 76E1, and S1 are colored in white, orange, and dark gray, respectively. S2 is in dim gray, of which IL770, FPPR, FP, and HR1 are colored as in Extended Data Fig. 5a, with S2′-helix in red. The distance is defined by the gap between the plane containing the centroid of each S2′-helix and another plane containing the centroid of each SD2. Using trimeric SD2 centroid as the vertex, the angle is defined by the deflection of one ACE2 molecule centroid in relation to the 3-fold axis. b, Left: Top view of the superposition of trimeric S1-ACE2 structures from apo D614G SE-FIC (gray) and WT SE-FIC-76E1 (colored as in Fig. 2a) after D614G-S1-ACE2 rotating (~8°) around the axis and shifting downward (~6 Å). Right: Side view of the superposition of S1-ACE2A. c, Left: Top view of the superposition of trimeric S1-ACE2 structures from WT SE-FIC-76E1 (gray) and XBB.1.5 SE-FIC-76E1 (colored as in Fig. 2a) after WT-S1-ACE2 rotating (~ 4°) around the axis and shifting upward (~3 Å). Right: Side view of the superposition of S1-ACE2A. In (b-c), arrows in arcs show rotations of ACE2A and each domain in S1A, relative to the trimeric SD2 centroid, while SD2 domain remains unchanged. d, Overall structure of the S2 trimer in the postfusion conformation (PDB 8FDW) shown as a ribbon diagram, colored as in Extended Data Fig. 5a. The S2′-helix epitope is indicated by a dashed box colored in lime. e, Clashes between the 76E1-Fab from XBB.1.5 SE-FIC-76E1 and the ACE2 from WT SE-FIC-76E1 can be avoided by reducing the antibody size into scFv.