Hydrophobic remodeling of the SARS-CoV-2 RBD large loop attenuates ACE2 engagement and viral fitness.

A475V in the SARS-CoV-2 Omicron JN.4 RBD large loop (residues 475–490) remodels the RBM and reduces ACE2-binding affinity 3.5-fold versus BA.2.86.

• Why it matters: Limited expansion of JN.4 versus JN.1 suggests that specific RBD changes can attenuate receptor engagement, but the structural basis for this tradeoff is unclear.
• What they did: Using cryo-electron microscopy with local refinement, plus systematic mutagenesis, molecular dynamics simulations, and functional assays, the study mapped how A475V reshapes RBD–ACE2 interaction geometry.
• The result: The bulky valine disrupts the interaction network around residue 475, and hydrophobic residues A475 and F486 are functionally constrained, implying the 475–490 loop balances recognition and conformational stability during adaptation.