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- PDB-6t13: CRYSTAL STRUCTURE OF GLUCOCEREBROSIDASE IN COMPLEX WITH A PYRROLO... -

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Basic information

Entry
Database: PDB / ID: 6t13
TitleCRYSTAL STRUCTURE OF GLUCOCEREBROSIDASE IN COMPLEX WITH A PYRROLOPYRAZINE
ComponentsGlucosylceramidase
KeywordsHYDROLASE / GCASE / GLYCOSIDASE / CEREZYME / HYDROLYSIS / GLYCOSYLCERAMIDASE
Function / homology
Function and homology information


negative regulation of macromolecule metabolic process / beta-glucoside catabolic process / steryl-beta-glucosidase activity / positive regulation of neuronal action potential / termination of signal transduction / galactosylceramidase / galactosylceramidase activity / lysosomal protein catabolic process / glucosylceramidase / response to thyroid hormone ...negative regulation of macromolecule metabolic process / beta-glucoside catabolic process / steryl-beta-glucosidase activity / positive regulation of neuronal action potential / termination of signal transduction / galactosylceramidase / galactosylceramidase activity / lysosomal protein catabolic process / glucosylceramidase / response to thyroid hormone / regulation of lysosomal protein catabolic process / scavenger receptor binding / glucosylceramide catabolic process / glycolipid biosynthetic process / sphingosine biosynthetic process / glucosylceramidase activity / glucosyltransferase activity / Glycosphingolipid catabolism / ceramide biosynthetic process / response to pH / regulation of TOR signaling / Hydrolases; Glycosylases; Glycosidases, i.e. enzymes that hydrolyse O- and S-glycosyl compounds / lysosome organization / regulation of protein catabolic process / Transferases; Glycosyltransferases; Hexosyltransferases / response to dexamethasone / beta-glucosidase activity / response to testosterone / negative regulation of interleukin-6 production / Association of TriC/CCT with target proteins during biosynthesis / establishment of skin barrier / cholesterol metabolic process / negative regulation of MAPK cascade / regulation of macroautophagy / protein catabolic process / lysosomal lumen / cellular response to starvation / trans-Golgi network / cellular response to tumor necrosis factor / regulation of membrane potential / negative regulation of inflammatory response / response to estrogen / autophagy / lysosome / signaling receptor binding / lysosomal membrane / Golgi apparatus / endoplasmic reticulum / extracellular exosome
Similarity search - Function
Glycosyl hydrolase family 30, TIM-barrel domain / Glycosyl hydrolase family 30 TIM-barrel domain / Glycosyl hydrolase family 30, beta sandwich domain / Glycosyl hydrolase family 30 beta sandwich domain / Glycoside hydrolase family 30 / Glycoside hydrolase superfamily
Similarity search - Domain/homology
Chem-M7H / Glucosylceramidase / Lysosomal acid glucosylceramidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.85 Å
AuthorsBenz, J. / Ehler, A. / Hug, M. / Huber, S. / Rufer, A.C. / Guba, W. / Jagasia, R. / Hofmann, E.C. / Rodriguez Sarmiento, R.M.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2021
Title: Novel beta-Glucocerebrosidase Activators That Bind to a New Pocket at a Dimer Interface and Induce Dimerization.
Authors: Benz, J. / Rufer, A.C. / Huber, S. / Ehler, A. / Hug, M. / Topp, A. / Guba, W. / Hofmann, E.C. / Jagasia, R. / Rodriguez Sarmiento, R.M.
History
DepositionOct 3, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 23, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 21, 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 24, 2024Group: 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
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glucosylceramidase
B: Glucosylceramidase
C: Glucosylceramidase
D: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)243,17638
Polymers239,0484
Non-polymers4,12834
Water26,5901476
1
A: Glucosylceramidase
D: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,70819
Polymers119,5242
Non-polymers2,18417
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5980 Å2
ΔGint-113 kcal/mol
Surface area35270 Å2
MethodPISA
2
B: Glucosylceramidase
C: Glucosylceramidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,46719
Polymers119,5242
Non-polymers1,94317
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5370 Å2
ΔGint-97 kcal/mol
Surface area34970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.849, 135.408, 191.384
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Glucosylceramidase


Mass: 59761.969 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: B2R6A7, UniProt: P04062*PLUS, glucosylceramidase

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Sugars , 2 types, 4 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 7 types, 1506 molecules

#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#8: Chemical ChemComp-M7H / 1-[4-[2-(4-methoxyphenyl)-5-methyl-pyrrolo[2,3-b]pyrazin-6-yl]piperidin-1-yl]ethanone


Mass: 364.441 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H24N4O2 / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1476 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.46 Å3/Da / Density % sol: 50.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 0.2M ammonium sulfate 0.1M Tris 17.5% PEG MME 5000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 22, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→191 Å / Num. obs: 201063 / % possible obs: 100 % / Redundancy: 6.79 % / Biso Wilson estimate: 34.28 Å2 / Rsym value: 0.08 / Net I/σ(I): 11.08
Reflection shellResolution: 1.85→1.94 Å / Num. unique obs: 26445 / Rsym value: 0.88

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XPREPdata scaling
PHASERphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1OGS

1ogs


Resolution: 1.85→48.71 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.953 / SU R Cruickshank DPI: 0.117 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.121 / SU Rfree Blow DPI: 0.113 / SU Rfree Cruickshank DPI: 0.111
RfactorNum. reflection% reflectionSelection details
Rfree0.204 9976 4.97 %RANDOM
Rwork0.174 ---
obs0.176 200850 99.9 %-
Displacement parametersBiso max: 202.47 Å2 / Biso mean: 53.68 Å2 / Biso min: 21.23 Å2
Baniso -1Baniso -2Baniso -3
1--10.073 Å20 Å20 Å2
2--6.6578 Å20 Å2
3---3.4152 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 1.85→48.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15695 0 254 1476 17425
Biso mean--61.31 55.88 -
Num. residues----1985
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d5391SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes2725HARMONIC5
X-RAY DIFFRACTIONt_it16441HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion2083SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact20250SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d16441HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg22422HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion3.91
X-RAY DIFFRACTIONt_other_torsion17.43
LS refinement shellResolution: 1.85→1.86 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.333 202 5.03 %
Rwork0.264 3815 -
all0.2674 4017 -
obs--99.83 %
Refinement TLS params.

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

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.41530.1904-0.04661.3582-0.29481.10220.0668-0.09140.06470.1014-0.08450.2833-0.2146-0.13320.0177-0.0725-0.00020.021-0.0933-0.0279-0.02121.0771-8.9945-2.7017
20.50740.1484-0.26421.2948-0.02241.25180.07240.13490.0205-0.27680.0056-0.1283-0.24590.0503-0.0780.04520.040.076-0.09980.0308-0.128237.7703-8.9694-36.6815
33.96781.46570.88093.352-0.06481.6786-0.56250.70230.8062-1.1750.27180.5001-0.19540.04910.29070.17380.0079-0.2711-0.39510.1653-0.31964.14299.2628-46.7176
40.90080.1079-0.40712.14050.82161.34350.1584-0.19220.11480.2585-0.0671-0.0349-0.14730.2107-0.09130.0782-0.1669-0.0029-0.1461-0.016-0.222432.255513.59795.1888
50.5575-0.3964-0.51410.90440.19130.56090.0201-0.00560.1070.0814-0.00890.2989-0.065-0.0359-0.01120.032-0.00430.0742-0.0508-0.030.0152000
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A1 - 497
2X-RAY DIFFRACTION2{ B|* }B1 - 497
3X-RAY DIFFRACTION3{ C|* }C1 - 497
4X-RAY DIFFRACTION4{ D|* }D1 - 497
5X-RAY DIFFRACTION5{ C|502 }C502
6X-RAY DIFFRACTION5{ D|502 }D502

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