ACE2–spike protein receptor-binding domain interface

The ACE2–spike RBD interface is the structurally defined molecular surface where the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein directly contacts the human ACE2 receptor, initiating viral attachment and subsequent entry into host cells. This interface involves critical amino acid residues from both ACE2 and spike RBD that mediate high-affinity binding through a combination of hydrogen bonds, salt bridges, and hydrophobic interactions[3][5]. The interface is a key determinant of viral infectiousness, transmissibility, and species specificity, and is central to the mechanism of neutralizing antibody activity. Therapeutic strategies targeting this interface include monoclonal antibodies and entry inhibitors designed to block the physical interaction, and all current COVID-19 vaccines aim to elicit an immune response against epitopes in or near this region[2][3][5]. Although termed a 'target', the interface itself is not a distinct protein or gene product but represents a transient protein–protein contact zone that can be structurally characterized and exploited in drug discovery. While the ACE2–spike RBD interface is a valid and highly relevant therapeutic target, it should be explicitly noted this is not a canonical molecular entity but rather an intermolecular interface between two proteins. Accurate database models should consider mapping this to its components ("Spike protein (S gene product)" and "Angiotensin-converting enzyme 2") with additional annotation for their interaction surface.

Other names

ACE2–spike interfacespike RBD–ACE2 interfaceSARS-CoV-2 entry interfaceS-protein:ACE2 binding site

Competitive inhibition (blockade of spike–ACE2 binding); Neutralization (antibody binding to RBD masking ACE2-contact surfaces); Conformational stabilization ("locking" spike protein conformations that prevent ACE2 engagement)