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- PDB-6srn: Structural basis for control of antibiotic production by bacteria... -

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Basic information

Entry
Database: PDB / ID: 6srn
TitleStructural basis for control of antibiotic production by bacterial hormones
ComponentsTetR family transcriptional regulator
KeywordsANTIBIOTIC / streptomyces / tetR-family transcriptional regulator / signalling / microbial natural product
Function / homology
Function and homology information


regulation of gene expression / DNA binding / identical protein binding
Similarity search - Function
Tetracyclin repressor-like, C-terminal domain superfamily / Bacterial regulatory proteins, tetR family / DNA-binding HTH domain, TetR-type / TetR-type HTH domain profile. / Homeobox-like domain superfamily
Similarity search - Domain/homology
4-(Hydroxymethyl)-2-propylfuran-3-carboxylic acid / TetR family transcriptional regulator
Similarity search - Component
Biological speciesStreptomyces coelicolor (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 1.5 Å
AuthorsFulop, V.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Royal SocietyUF090255 United Kingdom
Biotechnology and Biological Sciences Research CouncilBB/M022765/1 United Kingdom
Biotechnology and Biological Sciences Research CouncilBB/M017982/1 United Kingdom
CitationJournal: Nature / Year: 2021
Title: Molecular basis for control of antibiotic production by a bacterial hormone.
Authors: 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 / ...Authors: 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 / Christophe Corre /
Abstract: Actinobacteria produce numerous antibiotics and other specialized metabolites that have important applications in medicine and agriculture. Diffusible hormones frequently control the production of ...Actinobacteria produce numerous antibiotics and other specialized metabolites that have important applications in medicine and agriculture. Diffusible hormones frequently control the production of such metabolites by binding TetR family transcriptional repressors (TFTRs), but the molecular basis for this remains unclear. 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. 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.
History
DepositionSep 5, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 30, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: TetR family transcriptional regulator
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,3023
Polymers24,0231
Non-polymers2782
Water4,612256
1
A: TetR family transcriptional regulator
hetero molecules

A: TetR family transcriptional regulator
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,6036
Polymers48,0462
Non-polymers5574
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area3530 Å2
ΔGint-21 kcal/mol
Surface area16350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.210, 67.210, 92.820
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-302-

GOL

21A-576-

HOH

31A-655-

HOH

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Components

#1: Protein TetR family transcriptional regulator


Mass: 24023.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Streptomyces coelicolor (bacteria) / Gene: mmfR / Production host: Escherichia coli (E. coli) / References: UniProt: Q9JN89
#2: Chemical ChemComp-LUB / 4-(Hydroxymethyl)-2-propylfuran-3-carboxylic acid


Mass: 186.205 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H14O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 256 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.18 Å3/Da / Density % sol: 43.5 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / Details: 10-15% PEG 3350 and 0.2-0.25 M magnesium formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 17, 2011 / Details: MIRRORS
RadiationMonochromator: MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.5→42.34 Å / Num. obs: 34705 / % possible obs: 99.3 % / Observed criterion σ(I): -3 / Redundancy: 11.8 % / Rsym value: 0.082 / Net I/σ(I): 17.9
Reflection shellResolution: 1.5→1.58 Å / Num. unique obs: 1507 / Rsym value: 1.189 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XDSdata scaling
SOLVEphasing
RefinementMethod to determine structure: SAD / Resolution: 1.5→42.34 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.957 / SU B: 2.449 / SU ML: 0.048 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.068 / ESU R Free: 0.072
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2071 1417 4.1 %RANDOM
Rwork0.1738 ---
obs0.1751 33288 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 52.92 Å2 / Biso mean: 15.226 Å2 / Biso min: 4.88 Å2
Baniso -1Baniso -2Baniso -3
1--0.32 Å2-0 Å20 Å2
2---0.32 Å20 Å2
3---0.64 Å2
Refinement stepCycle: final / Resolution: 1.5→42.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1480 0 19 256 1755
Biso mean--16.75 32.33 -
Num. residues----187
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0191530
X-RAY DIFFRACTIONr_bond_other_d0.0010.021461
X-RAY DIFFRACTIONr_angle_refined_deg1.8621.9562068
X-RAY DIFFRACTIONr_angle_other_deg0.96933338
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3695186
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.82222.72777
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.07315251
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.0621517
X-RAY DIFFRACTIONr_chiral_restr0.1510.2222
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211749
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02373
LS refinement shellResolution: 1.5→1.539 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.24 90 -
Rwork0.267 2379 -
all-2469 -
obs--99.08 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
10.3134-0.99970.22534.73640.74171.5653-0.0553-0.00030.0010.36610.0726-0.05450.1010.0333-0.01740.11730.03150.00530.0466-0.01930.071318.33523.61129.597
21.2455-0.4943-0.15690.6589-0.04340.53710.01050.0992-0.0621-0.0283-0.00870.07840.159-0.0849-0.00180.0695-0.0081-0.00860.0578-0.01280.06764.5874323.253
30.46840.35550.25860.4981-0.26671.28940.0117-0.01850.03390.0234-0.03720.05370.0144-0.06060.02550.06120.01160.00070.0792-0.0120.08199.65152.83827.895
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A28 - 81
2X-RAY DIFFRACTION2A82 - 169
3X-RAY DIFFRACTION3A170 - 214

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