Structural Basis of SARS-CoV-2 Nsp13-Derived Peptide-Mediated NK Cell Activation.

As pivotal effectors of antiviral immunity, natural killer (NK) cells are crucial for controlling the spread of COVID-19. The nonstructural protein 13 of SARS-CoV-2 can encode a viral peptide (Nsp13) preventing human leukocyte antigen E (HLA-E) from recognizing inhibitory receptor NKG2A, thereby activating NK cells. The underlying molecular mechanisms of Nsp13 remain unclear. Therefore, we compared the interaction discrepancy between the self-peptide and Nsp13, theoretically predicting its source. Results indicate that electrostatic interaction energy provides the main source of binding, and its attenuation greatly promotes binding affinity differences. Nsp13 disrupts the hydrogen bond network between CD94 and HLA-E, impacting the binding of hot-spot residues, including Q112 and E161. Moreover, Nsp13 breaks the salt bridges formed by K217 and K199 with HLA-E. Conformational changes induced by Nsp13 lead to diminished atomic contacts and an unstable binding pattern. These findings provide novel insights into the immunomodulatory role of Nsp13 and may inform future NK cell-mediated strategies targeting SARS-CoV-2.