In all panels, the Class I RBD is colored magenta, the Class III, IV and V RBDs are colored cyan, and hAPN is colored gray. (a) Center: superimposition of the Class I, III IV and V RBD-hAPN complexes. Surrounding: the Class I and Class III RBDs are shown; the Class III RBD provides an example of the major differences observed between the Class III, IV and V RBDs relative to Class I. Loop 1, a twist in the loop allows Arg316 to interact with Asp288. Loop 2, a 2-aa deletion reorients Arg357, enabling a better interaction with Asp315. Loop 3, Leu402 and Leu405 replace Trp404, with Leu405 maintaining the apolar contact with Leu318. (b) The 315–320 segment of Loop 1shows a high degree of structural conservation among the four complexes. (c) Six hydrogen bonds (blue dotted lines, marked 1–6) are conserved among the four complexes and they all involve Loop 1 residues 315–320. Five of them (hydrogen bonds 1–5 in the figure) involve the five exposed backbone amide/carbonyl groups of hAPN residues 287–291; the sixth is formed with the sidechain of hAPN residue Asp 288. For clarity, only sidechains that participate in hydrogen bonds are shown. (d) Receptor binding loop sequence alignment. Differences relative to Class I are colored red. The six residues conserved among all HCoV-229E viruses sequenced are enclosed in blue boxes.