Structural basis of transcriptional activation by the Mycobacterium tuberculosis intrinsic antibiotic-resistance transcription factor WhiB7

Mol Cell. 2021 Jul 15;81(14):2875-2886.e5. doi: 10.1016/j.molcel.2021.05.017. Epub 2021 Jun 24.


In pathogenic mycobacteria, transcriptional responses to antibiotics result in induced antibiotic resistance. WhiB7 belongs to the Actinobacteria-specific family of Fe-S-containing transcription factors and plays a crucial role in inducible antibiotic resistance in mycobacteria. Here, we present cryoelectron microscopy structures of Mycobacterium tuberculosis transcriptional regulatory complexes comprising RNA polymerase σA-holoenzyme, global regulators CarD and RbpA, and WhiB7, bound to a WhiB7-regulated promoter. The structures reveal how WhiB7 interacts with σA-holoenzyme while simultaneously interacting with an AT-rich sequence element via its AT-hook. Evidently, AT-hooks, rare elements in bacteria yet prevalent in eukaryotes, bind to target AT-rich DNA sequences similarly to the nuclear chromosome binding proteins. Unexpectedly, a subset of particles contained a WhiB7-stabilized closed promoter complex, revealing this intermediate's structure, and we apply kinetic modeling and biochemical assays to rationalize how WhiB7 activates transcription. Altogether, our work presents a comprehensive view of how WhiB7 serves to activate gene expression leading to antibiotic resistance.

Keywords: RNA polymerase; WhiB7; antibiotic resistance; cryo-EM; iron cluster; transcription; transcription factor; transcription initiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / genetics*
  • Cryoelectron Microscopy / methods
  • DNA-Directed RNA Polymerases / genetics
  • Drug Resistance, Multiple, Bacterial / genetics*
  • Gene Expression Regulation, Bacterial / genetics
  • Intrinsic Factor / genetics*
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / genetics*
  • Promoter Regions, Genetic / genetics
  • Sigma Factor / genetics
  • Transcription Factors / genetics*
  • Transcriptional Activation / genetics*


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Sigma Factor
  • Transcription Factors
  • Intrinsic Factor
  • RNA polymerase sigma A
  • DNA-Directed RNA Polymerases