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

Abstract

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_232-240) preventing human leukocyte antigen E (HLA-E) from recognizing inhibitory receptor NKG2A, thereby activating NK cells. The underlying molecular mechanisms of Nsp13_232-240 remain unclear. Therefore, we compared the interaction discrepancy between the self-peptide and Nsp13_232-240, 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_232-240 disrupts the hydrogen bond network between CD94 and HLA-E, impacting the binding of hot-spot residues, including Q112_CD94 and E161_HLA-E. Moreover, Nsp13_232-240 breaks the salt bridges formed by K217_NKG2A and K199_NKG2A with HLA-E. Conformational changes induced by Nsp13_232-240 lead to diminished atomic contacts and an unstable binding pattern. These findings provide novel insights into the immunomodulatory role of Nsp13_232-240 and may inform future NK cell-mediated strategies targeting SARS-CoV-2.