Angiotensin-converting enzyme 2–SARS-CoV-2 spike protein interface (ACE2–SARS-CoV-2 S interface)

The ACE2–SARS-CoV-2 spike protein interface is the critical molecular contact point between the human host cell receptor angiotensin-converting enzyme 2 (ACE2) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein (Lan et al., Nature 2020). This protein-protein interaction (PPI) is the primary gateway for viral entry, as the binding of the S1 subunit to ACE2 triggers conformational changes that facilitate membrane fusion and the release of the viral genome into the cytoplasm (UniProt: P0DTC2). ACE2 normally functions as a carboxypeptidase that regulates the renin-angiotensin system by converting angiotensin II to angiotensin (1-7), providing cardioprotective and anti-inflammatory effects (UniProt: Q9BYF1). Therapeutic strategies targeting this interface primarily involve monoclonal antibodies that mask the RBD, preventing it from docking with ACE2, or decoy receptors that mimic ACE2 to sequester the virus (FDA EUA COVID-19 mAbs). Understanding the structural biology of this interface is essential for developing broad-spectrum antivirals and vaccines capable of overcoming viral evolution and mutational escape (PubMed: 32225176). The interface is characterized by a large surface area involving multiple polar and hydrophobic interactions, making it a challenging but high-value target for drug design (PubMed: 32142651).

Other names

ACE2-RBD interfaceSARS-CoV-2 spike-ACE2 complexSpike-ACE2 interaction siteHost-pathogen protein-protein interaction

Neutralizing antibodies and small molecules bind to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein or the extracellular domain of ACE2 to competitively inhibit the formation of the Spike-ACE2 complex, thereby preventing viral attachment and entry into host cells (PubMed: 32225176).