1. Molecular basis for control of antibiotic production by a bacterial hormone.
- Author
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Zhou S, Bhukya H, Malet N, Harrison PJ, Rea D, Belousoff MJ, Venugopal H, Sydor PK, Styles KM, Song L, Cryle MJ, Alkhalaf LM, Fülöp V, Challis GL, and Corre C
- Subjects
- Apoproteins chemistry, Apoproteins metabolism, Apoproteins ultrastructure, Bacterial Proteins chemistry, Bacterial Proteins classification, Bacterial Proteins metabolism, Bacterial Proteins ultrastructure, Cryoelectron Microscopy, Crystallography, X-Ray, DNA chemistry, DNA genetics, DNA metabolism, DNA ultrastructure, Furans chemistry, Hormones chemistry, Hormones classification, Hormones metabolism, Ligands, Models, Molecular, Peptides metabolism, Repressor Proteins chemistry, Repressor Proteins classification, Repressor Proteins metabolism, Repressor Proteins ultrastructure, Signal Transduction, Streptomyces coelicolor chemistry, Streptomyces coelicolor genetics, Structure-Activity Relationship, Anti-Bacterial Agents biosynthesis, Furans metabolism, Streptomyces coelicolor metabolism
- Abstract
Actinobacteria produce numerous antibiotics and other specialized metabolites that have important applications in medicine and agriculture
1 . 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.- Published
- 2021
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