Molecular basis for control of antibiotic production by a bacterial hormone.

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Tytuł:: Molecular basis for control of antibiotic production by a bacterial hormone.
Autorzy:: Zhou S; Department of Chemistry, University of Warwick, Coventry, UK.
Bhukya H; Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Malet N; Department of Chemistry, University of Warwick, Coventry, UK.
Harrison PJ; Department of Chemistry, University of Warwick, Coventry, UK.
Rea D; School of Life Sciences, University of Warwick, Coventry, UK.
Belousoff MJ; Infection and Immunity Program, Department of Microbiology, Monash University, Clayton, Victoria, Australia.
Venugopal H; Ramaciotti Centre for Electron Microscopy, Monash University, Clayton, Victoria, Australia.
Sydor PK; Department of Chemistry, University of Warwick, Coventry, UK.
Styles KM; School of Life Sciences, University of Warwick, Coventry, UK.
Song L; Department of Chemistry, University of Warwick, Coventry, UK.
Cryle MJ; Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.; ARC Centre of Excellence for Innovations in Peptide and Protein Science, Monash University, Clayton, Victoria, Australia.
Alkhalaf LM; Department of Chemistry, University of Warwick, Coventry, UK.
Fülöp V; School of Life Sciences, University of Warwick, Coventry, UK.
Challis GL; Department of Chemistry, University of Warwick, Coventry, UK. .; Warwick Integrative Synthetic Biology Centre, University of Warwick, Coventry, UK. .; Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. .; ARC Centre of Excellence for Innovations in Peptide and Protein Science, Monash University, Clayton, Victoria, Australia. .
Corre C; Department of Chemistry, University of Warwick, Coventry, UK. .; School of Life Sciences, University of Warwick, Coventry, UK. .; Warwick Integrative Synthetic Biology Centre, University of Warwick, Coventry, UK. .
Źródło:: Nature [Nature] 2021 Feb; Vol. 590 (7846), pp. 463-467. Date of Electronic Publication: 2021 Feb 03.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
MeSH Terms:: Anti-Bacterial Agents/*biosynthesis
Furans/*metabolism
Streptomyces coelicolor/*metabolism
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
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Grant Information:: BB/M017982/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council
Substance Nomenclature:: 0 (Anti-Bacterial Agents)
0 (Apoproteins)
0 (Bacterial Proteins)
0 (Furans)
0 (Hormones)
0 (Ligands)
0 (Peptides)
0 (Repressor Proteins)
9007-49-2 (DNA)
X902U0148F (methylenomycin A)
Entry Date(s):: Date Created: 20210204 Date Completed: 20210312 Latest Revision: 20220323
Update Code:: 20240105
DOI:: 10.1038/s41586-021-03195-x
PMID:: 33536618
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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 unclear 2 . 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 MmfR 3 . 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.

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