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- PDB-6cxs: Crystal Structure of Clostridium perfringens beta-glucuronidase b... -

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Basic information

Entry
Database: PDB / ID: 6cxs
TitleCrystal Structure of Clostridium perfringens beta-glucuronidase bound with a novel, potent inhibitor 4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4',5':4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine
Components
  • Beta-glucuronidase
  • Maltose/maltodextrin-binding periplasmic protein
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE-HYDROLASE-INHIBITOR complex / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


beta-glucuronidase / beta-galactosidase activity / detection of maltose stimulus / maltose transport complex / carbohydrate transport / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing ...beta-glucuronidase / beta-galactosidase activity / detection of maltose stimulus / maltose transport complex / carbohydrate transport / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / outer membrane-bounded periplasmic space / carbohydrate metabolic process / periplasmic space / DNA damage response / membrane
Similarity search - Function
Glycoside hydrolase, family 2, active site / Glycosyl hydrolases family 2 acid/base catalyst. / Glycoside hydrolase, family 2, conserved site / Glycosyl hydrolases family 2 signature 1. / Glycoside hydrolase, family 2 / Glycoside hydrolase family 2, catalytic domain / Glycosyl hydrolases family 2, TIM barrel domain / Glycoside hydrolase, family 2, immunoglobulin-like beta-sandwich / Glycosyl hydrolases family 2, sugar binding domain / Glycosyl hydrolases family 2 ...Glycoside hydrolase, family 2, active site / Glycosyl hydrolases family 2 acid/base catalyst. / Glycoside hydrolase, family 2, conserved site / Glycosyl hydrolases family 2 signature 1. / Glycoside hydrolase, family 2 / Glycoside hydrolase family 2, catalytic domain / Glycosyl hydrolases family 2, TIM barrel domain / Glycoside hydrolase, family 2, immunoglobulin-like beta-sandwich / Glycosyl hydrolases family 2, sugar binding domain / Glycosyl hydrolases family 2 / Glycosyl hydrolases family 2, sugar binding domain / Beta-Galactosidase/glucuronidase domain superfamily / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Galactose-binding domain-like / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / Galactose-binding-like domain superfamily / Glycosidases / Glycoside hydrolase superfamily / Jelly Rolls / TIM Barrel / Alpha-Beta Barrel / Immunoglobulin-like fold / Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-FJV / Maltose/maltodextrin-binding periplasmic protein / Beta-glucuronidase
Similarity search - Component
Biological speciesClostridium perfringens (bacteria)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsWallace, B.D. / Redinbo, M.R.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2020
Title: Targeted inhibition of gut bacterial beta-glucuronidase activity enhances anticancer drug efficacy.
Authors: Bhatt, A.P. / Pellock, S.J. / Biernat, K.A. / Walton, W.G. / Wallace, B.D. / Creekmore, B.C. / Letertre, M.M. / Swann, J.R. / Wilson, I.D. / Roques, J.R. / Darr, D.B. / Bailey, S.T. / ...Authors: Bhatt, A.P. / Pellock, S.J. / Biernat, K.A. / Walton, W.G. / Wallace, B.D. / Creekmore, B.C. / Letertre, M.M. / Swann, J.R. / Wilson, I.D. / Roques, J.R. / Darr, D.B. / Bailey, S.T. / Montgomery, S.A. / Roach, J.M. / Azcarate-Peril, M.A. / Sartor, R.B. / Gharaibeh, R.Z. / Bultman, S.J. / Redinbo, M.R.
History
DepositionApr 4, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 11, 2020Group: 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.title / _citation.year
Revision 1.2Mar 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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: Beta-glucuronidase
B: Beta-glucuronidase
C: Maltose/maltodextrin-binding periplasmic protein
D: Maltose/maltodextrin-binding periplasmic protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)226,9846
Polymers226,1614
Non-polymers8232
Water6,215345
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6510 Å2
ΔGint-19 kcal/mol
Surface area70100 Å2
2
A: Beta-glucuronidase
B: Beta-glucuronidase
hetero molecules

A: Beta-glucuronidase
B: Beta-glucuronidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)277,9958
Polymers276,3494
Non-polymers1,6464
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_455-x-1,y,-z+1/21
Buried area16390 Å2
ΔGint-110 kcal/mol
Surface area80330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.289, 292.091, 240.471
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-750-

HOH

21A-892-

HOH

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Components

#1: Protein Beta-glucuronidase


Mass: 69087.125 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Clostridium perfringens (strain 13 / Type A) (bacteria)
Strain: 13 / Type A / Gene: bglR / Production host: Escherichia coli (E. coli) / References: UniProt: Q8XP19
#2: Protein Maltose/maltodextrin-binding periplasmic protein / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP


Mass: 43993.242 Da / Num. of mol.: 2 / Fragment: residues 27-392
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli) / Strain: K12 / Gene: malE, b4034, JW3994 / Production host: Escherichia coli (E. coli) / References: UniProt: P0AEX9
#3: Chemical ChemComp-FJV / 4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4',5':4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine / 5-(morpholin-4-yl)-8-(piperazin-1-yl)-1,2,3,4-tetrahydro[1,2,3]triazino[4',5':4,5]thieno[2,3-c]isoquinoline


Mass: 411.524 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H25N7OS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 345 / Source method: isolated from a natural source / Formula: H2O

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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: 3.02 Å3/Da / Density % sol: 59.29 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / Details: 0.1 M MES, 28-36% PEG 400 / PH range: 6.0-6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Aug 8, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.688→48.682 Å / Num. all: 69596 / Num. obs: 69596 / % possible obs: 99.1 % / Redundancy: 4.7 % / Biso Wilson estimate: 60.45 Å2 / Rpim(I) all: 0.05 / Rrim(I) all: 0.114 / Rsym value: 0.101 / Net I/av σ(I): 6.4 / Net I/σ(I): 11.1 / Num. measured all: 327990
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.69-2.834.80.9030.848323101540.4371.0110.9031.999.9
2.83-3.014.80.5891.24579296070.290.6620.589399.8
3.01-3.214.80.35624302590340.1770.4010.3564.899.8
3.21-3.474.80.2043.53995483700.1010.2290.2047.899.5
3.47-3.84.70.1176.23662877310.0580.1310.11711.999.2
3.8-4.254.70.0729.83294169880.0350.080.07216.898.9
4.25-4.914.70.05612.12878461720.0270.0630.0562198.6
4.91-6.014.60.05312.22413452310.0260.0590.05321.698
6.01-8.54.60.04912.31845040340.0230.0550.04923.497.4
8.5-48.6824.40.0413.5995922750.0190.0450.0430.495.1

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
SCALA3.3.20data scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4JKM

4jkm


Resolution: 2.8→48.682 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 23.16 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.236 3117 5.06 %
Rwork0.1996 58492 -
obs0.2014 61609 98.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 156.55 Å2 / Biso mean: 61.0749 Å2 / Biso min: 21.24 Å2
Refinement stepCycle: final / Resolution: 2.8→48.682 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14190 0 58 346 14594
Biso mean--66.18 50.93 -
Num. residues----1811
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 22

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8-2.84380.291300.2627012831100
2.8438-2.89040.31211450.246226362781100
2.8904-2.94020.32131360.249526412777100
2.9402-2.99370.26291350.252126562791100
2.9937-3.05120.29061280.245826712799100
3.0512-3.11350.29671430.250826852828100
3.1135-3.18120.31471300.242226292759100
3.1812-3.25520.26241380.23062679281799
3.2552-3.33660.2751670.219626282795100
3.3366-3.42680.241350.20992651278699
3.4268-3.52760.27821220.20762659278199
3.5276-3.64140.24961570.20792626278399
3.6414-3.77150.24661480.19942666281499
3.7715-3.92240.22011160.18872690280699
3.9224-4.10090.21931510.182614276599
4.1009-4.31690.22291630.18042638280198
4.3169-4.58720.20471320.16982666279898
4.5872-4.94110.20081430.15972649279298
4.9411-5.43770.18571600.17512655281598
5.4377-6.22320.22731510.1962636278797
6.2232-7.83530.24271380.20362689282797
7.8353-48.68920.22141490.19772727287694

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