Optimization of the NFκB-DNA ensemble leads to high affinity binding of partial consensus sites

Rearranging nucleotides at the RelA-interacting end to form a half-site induces dynamic structural changes across both RelA and p50, enabling high-affinity NFκB binding to partial consensus DNA.

• Why it matters: NFκB (RelA/p50) binds many nonconsensus sequences in vivo, yet the structural mechanism by which half-sites achieve strong binding remains unclear.
• What they did: Using hydrogen deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations, the study compared NFκB binding to consensus versus half-site DNA sequences.
• The result: MD simulations show a shift in DNA position within the RelA/p50 binding pocket that supports optimal interactions with the half-site, explaining high-affinity binding to multiple target sequences.