Chen, WeiLu, WeiWolynes, Peter GKomives, Elizabeth A2021-12-152021-12-152021Chen, Wei, Lu, Wei, Wolynes, Peter G, et al.. "Single-molecule conformational dynamics of a transcription factor reveals a continuum of binding modes controlling association and dissociation." <i>Nucleic Acids Research,</i> 49, no. 19 (2021) Oxford University Press: 11211-11223. https://doi.org/10.1093/nar/gkab874.https://hdl.handle.net/1911/111794Binding and unbinding of transcription factors to DNA are kinetically controlled to regulate the transcriptional outcome. Control of the release of the transcription factor NF-κB from DNA is achieved through accelerated dissociation by the inhibitor protein IκBα. Using single-molecule FRET, we observed a continuum of conformations of NF-κB in free and DNA-bound states interconverting on the subseconds to minutes timescale, comparable to in vivo binding on the seconds timescale, suggesting that structural dynamics directly control binding kinetics. Much of the DNA-bound NF-κB is partially bound, allowing IκBα invasion to facilitate DNA dissociation. IκBα induces a locked conformation where the DNA-binding domains of NF-κB are too far apart to bind DNA, whereas a loss-of-function IκBα mutant retains the NF-κB conformational ensemble. Overall, our results suggest a novel mechanism with a continuum of binding modes for controlling association and dissociation of transcription factors.engThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Journal articlegkab874https://doi.org/10.1093/nar/gkab874