Tuning site-specific dynamics to drive allosteric activation in a pneumococcal zinc uptake regulator.

Abstract

MarR (multiple antibiotic resistance repressor) family proteins are bacterial repressors that regulate transcription in response to a wide range of chemical signals. Although specific features of MarR family function have been described, the role of atomic motions in MarRs remains unexplored thus limiting insights into the evolution of allostery in this ubiquitous family of repressors. Here, we provide the first experimental evidence that internal dynamics play a crucial functional role in MarR proteins. <i>Streptococcus pneumoniae</i> AdcR (adhesin-competence repressor) regulates Zn^II homeostasis and Zn^II functions as an allosteric activator of DNA binding. Zn^II coordination triggers a transition from somewhat independent domains to a more compact structure. We identify residues that impact allosteric activation on the basis of Zn^II-induced perturbations of atomic motions over a wide range of timescales. These findings appear to reconcile the distinct allosteric mechanisms proposed for other MarRs and highlight the importance of conformational dynamics in biological regulation.