Molecular basis for control of antibiotic production by a bacterial hormone

Shanshan Zhou, Hussain Bhukya, Nicolas Malet, Peter J. Harrison, Dean Rea, Matthew J. Belousoff, Hariprasad Venugopal, Paulina K. Sydor, Kathryn M. Styles, Lijiang Song, Max J. Cryle, Lona M. Alkhalaf, Vilmos Fülöp, Gregory L. Challis () and Christophe Corre ()
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Shanshan Zhou: University of Warwick
Hussain Bhukya: Monash University
Nicolas Malet: University of Warwick
Peter J. Harrison: University of Warwick
Dean Rea: University of Warwick
Matthew J. Belousoff: Monash University
Hariprasad Venugopal: Monash University
Paulina K. Sydor: University of Warwick
Kathryn M. Styles: University of Warwick
Lijiang Song: University of Warwick
Max J. Cryle: Monash University
Lona M. Alkhalaf: University of Warwick
Vilmos Fülöp: University of Warwick
Gregory L. Challis: University of Warwick
Christophe Corre: University of Warwick

Nature, 2021, vol. 590, issue 7846, 463-467

Abstract: Abstract Actinobacteria produce numerous antibiotics and other specialized metabolites that have important applications in medicine and agriculture1. Diffusible hormones frequently control the production of such metabolites by binding TetR family transcriptional repressors (TFTRs), but the molecular basis for this remains unclear2. The production of methylenomycin antibiotics in Streptomyces coelicolor A3(2) is initiated by the binding of 2-alkyl-4-hydroxymethylfuran-3-carboxylic acid (AHFCA) hormones to the TFTR MmfR3. Here we report the X-ray crystal structure of an MmfR–AHFCA complex, establishing the structural basis for hormone recognition. We also elucidate the mechanism for DNA release upon hormone binding through the single-particle cryo-electron microscopy structure of an MmfR–operator complex. DNA binding and release assays with MmfR mutants and synthetic AHFCA analogues define the role of individual amino acid residues and hormone functional groups in ligand recognition and DNA release. These findings will facilitate the exploitation of actinobacterial hormones and their associated TFTRs in synthetic biology and in the discovery of new antibiotics.

Date: 2021
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DOI: 10.1038/s41586-021-03195-x

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