Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein – Angiotensin-converting enzyme 2 (ACE2) protein-protein interface (SARS-CoV-2 S – ACE2 PPI)

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein – Angiotensin-converting enzyme 2 (ACE2) protein-protein interface is the critical site of interaction that facilitates the entry of the SARS-CoV-2 virus into human host cells (UniProt P0DTC2, Q9BYF1). The viral spike (S) protein, specifically its receptor-binding domain (RBD), recognizes and binds to the extracellular peptidase domain of the ACE2 receptor, which is highly expressed in the lungs, heart, and other tissues (NCBI PMC7224615). This binding event triggers a conformational change in the spike protein, leading to membrane fusion and the release of the viral genome into the cytoplasm (PubMed 32142651). Because this interface is essential for the initiation of the viral life cycle, it has become a primary target for therapeutic intervention (NIH). Drugs targeting this interface, such as neutralizing monoclonal antibodies and soluble ACE2 decoys, aim to block the physical interaction between the virus and the host cell (FDA). However, the rapid evolution of the spike protein, particularly within the RBD, poses a significant challenge as mutations can reduce the binding affinity of existing therapeutics, leading to viral escape (Nature 591, 639–644).

Other names

SARS-CoV-2 S-ACE2 interfaceSpike-ACE2 interactionRBD-ACE2 interfaceSARS-CoV-2 receptor binding domain-ACE2 complex

Neutralizing antibodies or decoy receptors bind to the receptor-binding domain (RBD) of the spike protein or the binding surface of ACE2 to sterically block the protein-protein interaction, preventing viral attachment and subsequent entry into host cells (FDA, PubMed 32275855).