ACE2 binds to the tip of the SARS-CoV spike trimer, where S1-CTD is located. Because the membrane-distal tips of the trimeric spike are the most exposed and protruding region on the whole spike, S1-CTD is directly exposed to the host immune system, evolves at an increased pace to evade the host immune surveillance, and becomes hypervariable in primary, secondary, and tertiary structures.
