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- PDB-6xkd: Structure of ligand-bound mouse cGAMP hydrolase ENPP1 -

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Basic information

Entry
Database: PDB / ID: 6xkd
TitleStructure of ligand-bound mouse cGAMP hydrolase ENPP1
ComponentsEctonucleotide pyrophosphatase/phosphodiesterase family member 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / hydrolase / inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


scavenger receptor activity / hydrolase activity, acting on ester bonds / polysaccharide binding / nucleic acid binding / immune response / extracellular region / membrane / metal ion binding
Similarity search - Function
Somatomedin B domain, chordata / Somatomedin B -like domains / Somatomedin B domain / Somatomedin B-like domain superfamily / Somatomedin B domain / Somatomedin B domain (SMB) signature. / Somatomedin B (SMB) domain profile. / Type I phosphodiesterase/nucleotide pyrophosphatase/phosphate transferase / Type I phosphodiesterase / nucleotide pyrophosphatase / Extracellular Endonuclease, subunit A ...Somatomedin B domain, chordata / Somatomedin B -like domains / Somatomedin B domain / Somatomedin B-like domain superfamily / Somatomedin B domain / Somatomedin B domain (SMB) signature. / Somatomedin B (SMB) domain profile. / Type I phosphodiesterase/nucleotide pyrophosphatase/phosphate transferase / Type I phosphodiesterase / nucleotide pyrophosphatase / Extracellular Endonuclease, subunit A / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease / DNA/RNA non-specific endonuclease superfamily / His-Me finger superfamily / Alkaline-phosphatase-like, core domain superfamily
Similarity search - Domain/homology
Chem-IJE / Ectonucleotide pyrophosphatase/phosphodiesterase 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.2 Å
AuthorsFernandez, D. / Li, L.
CitationJournal: Cell Chem Biol / Year: 2020
Title: Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP.
Authors: Carozza, J.A. / Brown, J.A. / Bohnert, V. / Fernandez, D. / AlSaif, Y. / Mardjuki, R.E. / Smith, M. / Li, L.
History
DepositionJun 26, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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

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Assembly

Deposited unit
A: Ectonucleotide pyrophosphatase/phosphodiesterase family member 1
B: Ectonucleotide pyrophosphatase/phosphodiesterase family member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)191,81914
Polymers189,1202
Non-polymers2,69812
Water57632
1
A: Ectonucleotide pyrophosphatase/phosphodiesterase family member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,3399
Polymers94,5601
Non-polymers1,7798
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Ectonucleotide pyrophosphatase/phosphodiesterase family member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,4805
Polymers94,5601
Non-polymers9204
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.350, 102.350, 172.891
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Ectonucleotide pyrophosphatase/phosphodiesterase family member 1


Mass: 94560.203 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Enpp1 / Production host: Homo sapiens (human) / References: UniProt: G3X9S2

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Sugars , 2 types, 4 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#3: 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.: 2
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 , 5 types, 40 molecules

#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: Zn
#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-IJE / {2-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl}phosphonic acid


Mass: 381.363 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H24N3O5P / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Nonpolymer detailsThe authors state that the zinc-binding group and hydrophobic core of the inhibitor have weak ...The authors state that the zinc-binding group and hydrophobic core of the inhibitor have weak density in the binding pocket of ENPP1. The piperidinyl linker moiety shows very weak density apparently because of high flexibility of the hydrocarbon and it being exposed to the solvent. In polypeptide chain A the inhibitor was modeled with 0.5 occupancy. Trace of inhibitor in the electron density appears to be present in polypeptide B chain but the density is very weak and the inhibitor wasn't modeled there.

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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: 2.76 Å3/Da / Density % sol: 55.51 % / Description: Needle
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: PEG 600, sodium acetate, magnesium acetate, polyvinylpyrrolidone

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Sep 22, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 3.2→88.638 Å / Num. all: 30691 / Num. obs: 30691 / % possible obs: 91.8 % / Redundancy: 2.1 % / Rpim(I) all: 0.124 / Rrim(I) all: 0.204 / Rsym value: 0.16 / Net I/av σ(I): 3.8 / Net I/σ(I): 5.4 / Num. measured all: 65417
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
3.2-3.372.10.7230.8906143930.5730.9270.7231.890.6
3.37-3.582.10.4411.4905442640.3390.560.4412.692
3.58-3.822.20.292.1877140410.2230.3680.293.892.8
3.82-4.132.20.1973.3807837160.1510.250.197591.8
4.13-4.532.10.1215.4692033730.0940.1540.1216.491.1
4.53-5.062.20.1016.5673531070.0780.1280.1017.592
5.06-5.842.20.16.6610627530.0750.1250.17.493.5
5.84-7.162.10.0867.4467422760.0680.1110.0867.990.3
7.16-10.122.20.0747.9398318140.0580.0950.07410.193.5
10.12-86.4462.10.0678.620359540.0520.0860.06711.189.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
MOSFLMdata reduction
PHASERphasing
PDB_EXTRACT3.25data extraction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4gtw

4gtw


Resolution: 3.2→30.64 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.848 / SU B: 28.054 / SU ML: 0.457 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.56 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2733 1518 5 %RANDOM
Rwork0.2014 ---
obs0.205 29094 91.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 138.87 Å2 / Biso mean: 63.997 Å2 / Biso min: 19.6 Å2
Baniso -1Baniso -2Baniso -3
1-1.25 Å20.63 Å20 Å2
2--1.25 Å20 Å2
3----4.07 Å2
Refinement stepCycle: final / Resolution: 3.2→30.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10682 0 161 32 10875
Biso mean--84.25 36.44 -
Num. residues----1360
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.01911186
X-RAY DIFFRACTIONr_angle_refined_deg1.4051.98115278
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4251345
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.00223.875480
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.987151674
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.8831543
X-RAY DIFFRACTIONr_chiral_restr0.0880.21700
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0218498
LS refinement shellResolution: 3.2→3.282 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.37 111 -
Rwork0.296 2081 -
all-2192 -
obs--90.54 %

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