{Reference Type}: Journal Article
{Title}: Structure and inhibition of SARS-CoV-2 spike refolding in membranes.
{Author}: Grunst MW;Qin Z;Dodero-Rojas E;Ding S;Prévost J;Chen Y;Hu Y;Pazgier M;Wu S;Xie X;Finzi A;Onuchic JN;Whitford PC;Mothes W;Li W;
{Journal}: Science
{Volume}: 385
{Issue}: 6710
{Year}: 2024 Aug 16
{Factor}: 63.714
{DOI}: 10.1126/science.adn5658
{Abstract}: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the receptor angiotensin converting enzyme 2 (ACE2) and drives virus-host membrane fusion through refolding of its S2 domain. Whereas the S1 domain contains high sequence variability, the S2 domain is conserved and is a promising pan-betacoronavirus vaccine target. We applied cryo-electron tomography to capture intermediates of S2 refolding and understand inhibition by antibodies to the S2 stem-helix. Subtomogram averaging revealed ACE2 dimers cross-linking spikes before transitioning into S2 intermediates, which were captured at various stages of refolding. Pan-betacoronavirus neutralizing antibodies targeting the S2 stem-helix bound to and inhibited refolding of spike prehairpin intermediates. Combined with molecular dynamics simulations, these structures elucidate the process of SARS-CoV-2 entry and reveal how pan-betacoronavirus S2-targeting antibodies neutralize infectivity by arresting prehairpin intermediates.