Structural basis of the mercury(II)-mediated conformational switching of the dual-function transcriptional regulator MerR

摘要

The mer operon confers bacterial resistance to inorganic mercury (Hg²⁺) and organomercurials by encoding proteins involved in sensing, transport and detoxification of these cytotoxic agents. Expression of the mer operon is under tight control by the dual-function transcriptional regulator MerR. The metal-free, apo MerR binds to the mer operator/promoter region as a repressor to block transcription initiation, but is converted into an activator upon Hg²⁺-binding. To understand how MerR interacts with Hg²⁺ and how Hg²⁺-binding modulates MerR function, we report here the crystal structures of apo and Hg²⁺-bound MerR from Bacillus megaterium, corresponding respectively to the repressor and activator conformation of MerR. To our knowledge, the apo-MerR structure represents the first visualization of a MerR family member in its intact and inducer-free form. And the Hg²⁺-MerR structure offers the first view of a triligated Hg²⁺-thiolate center in a metalloprotein, confirming that MerR binds Hg²⁺ via trigonal planar coordination geometry. Structural comparison revealed the conformational transition of MerR is coupled to the assembly/disassembly of a buried Hg²⁺ binding site, thereby providing a structural basis for the Hg²⁺-mediated functional switching of MerR. The pronounced Hg²⁺-induced repositioning of the MerR DNA-binding domains suggests a plausible mechanism for the transcriptional regulation of the mer operon.