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- PDB-6ye1: Human Ecto-5'-nucleotidase (CD73) in complex with the AMPCP deriv... -

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Basic information

Entry
Database: PDB / ID: 6ye1
TitleHuman Ecto-5'-nucleotidase (CD73) in complex with the AMPCP derivative A894 (compound 2n in publication) in the closed form (crystal form IV)
Components5'-nucleotidase
KeywordsHYDROLASE / competitive nucleotide inhibitor
Function / homology
Function and homology information


thymidylate 5'-phosphatase / thymidylate 5'-phosphatase activity / ADP catabolic process / 5'-deoxynucleotidase / 5'-deoxynucleotidase activity / 7-methylguanosine nucleotidase / inhibition of non-skeletal tissue mineralization / adenosine biosynthetic process / Pyrimidine catabolism / AMP catabolic process ...thymidylate 5'-phosphatase / thymidylate 5'-phosphatase activity / ADP catabolic process / 5'-deoxynucleotidase / 5'-deoxynucleotidase activity / 7-methylguanosine nucleotidase / inhibition of non-skeletal tissue mineralization / adenosine biosynthetic process / Pyrimidine catabolism / AMP catabolic process / GMP 5'-nucleotidase activity / IMP-specific 5'-nucleotidase / IMP 5'-nucleotidase activity / Nicotinate metabolism / Purine catabolism / XMP 5'-nucleosidase activity / 5'-nucleotidase / 5'-nucleotidase activity / DNA metabolic process / leukocyte cell-cell adhesion / response to ATP / response to inorganic substance / calcium ion homeostasis / Purinergic signaling in leishmaniasis infection / ATP metabolic process / negative regulation of inflammatory response / external side of plasma membrane / nucleotide binding / cell surface / extracellular exosome / zinc ion binding / nucleoplasm / membrane / identical protein binding / plasma membrane / cytosol
Similarity search - Function
5'-nucleotidase signature 1. / 5'-Nucleotidase, conserved site / 5'-nucleotidase signature 2. / 5'-Nucleotidase, C-terminal / 5'-nucleotidase, C-terminal domain / 5'-Nucleotidase/apyrase / 5'-Nucleotidase, C-terminal domain superfamily / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Metallo-dependent phosphatase-like
Similarity search - Domain/homology
Chem-OO2 / 5'-nucleotidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.66 Å
Model detailsThe compound is a competitive non-nucleotide inhibitor binding to the active site
AuthorsScaletti, E. / Strater, N.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors.
Authors: Sharif, E.U. / Kalisiak, J. / Lawson, K.V. / Miles, D.H. / Newcomb, E. / Lindsey, E.A. / Rosen, B.R. / Debien, L.P.P. / Chen, A. / Zhao, X. / Young, S.W. / Walker, N.P. / Strater, N. / ...Authors: Sharif, E.U. / Kalisiak, J. / Lawson, K.V. / Miles, D.H. / Newcomb, E. / Lindsey, E.A. / Rosen, B.R. / Debien, L.P.P. / Chen, A. / Zhao, X. / Young, S.W. / Walker, N.P. / Strater, N. / Scaletti, E.R. / Jin, L. / Xu, G. / Leleti, M.R. / Powers, J.P.
History
DepositionMar 23, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 27, 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 1.2Jan 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 5'-nucleotidase
B: 5'-nucleotidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,7108
Polymers118,5212
Non-polymers1,1896
Water5,188288
1
B: 5'-nucleotidase
hetero molecules

A: 5'-nucleotidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,7108
Polymers118,5212
Non-polymers1,1896
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_556x+1/2,-y+1/2,-z+11
Buried area2650 Å2
ΔGint-58 kcal/mol
Surface area40280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.030, 232.120, 53.790
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein 5'-nucleotidase / / 5'-NT / Ecto-5'-nucleotidase


Mass: 59260.406 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NT5E, NT5, NTE / Production host: Escherichia coli (E. coli) / References: UniProt: P21589, 5'-nucleotidase
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-OO2 / [(2~{R},3~{S},4~{R},5~{R})-5-[2-chloranyl-6-(cyclopentylamino)purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methoxymethylphosphonic acid


Mass: 463.810 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H23ClN5O7P / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 288 / 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: 2.45 Å3/Da / Density % sol: 49.8 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 1mM of compound, 0.1 mM ZnCl2, 11-14% PEG6000, 100 mM sodium citrate pH 5.4-5.6, 15% glycerol for cryo
PH range: 5.4-5.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 23, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.66→46.52 Å / Num. obs: 34420 / % possible obs: 99.6 % / Redundancy: 6.531 % / Biso Wilson estimate: 45.71 Å2 / CC1/2: 0.991 / Rmerge(I) obs: 0.253 / Rrim(I) all: 0.275 / Χ2: 0.949 / Net I/σ(I): 6.99 / Num. measured all: 224786
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.66-2.826.5150.8671.9535411549654350.4870.94398.9
2.82-3.016.6210.7262.534139515951560.6460.78899.9
3.01-3.256.7950.5683.3832489478847810.8420.61699.9
3.25-3.566.3140.394.7828254448744750.9430.42599.7
3.56-3.986.7960.2567.4627382403540290.9820.27799.9
3.98-4.596.4580.15410.9423171360535880.9930.16799.5
4.59-5.616.6280.11813.6220195306630470.9950.12899.4
5.61-7.886.2310.11613.215267245924500.9950.12799.6
7.88-46.525.8110.04925.028478148014590.9990.05498.6

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Processing

Software
NameVersionClassification
XSCALEdata scaling
BUSTER2.10.3refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4H2I
Resolution: 2.66→46.52 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.877 / SU R Cruickshank DPI: 2.594 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.355 / SU Rfree Cruickshank DPI: 0.354
RfactorNum. reflection% reflectionSelection details
Rfree0.268 1721 5 %RANDOM
Rwork0.193 ---
obs0.197 34401 99.4 %-
Displacement parametersBiso max: 147.12 Å2 / Biso mean: 58.63 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--3.5489 Å20 Å20 Å2
2--1.5439 Å20 Å2
3---2.0049 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: final / Resolution: 2.66→46.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8153 0 64 288 8505
Biso mean--55.85 31.1 -
Num. residues----1045
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2946SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1452HARMONIC5
X-RAY DIFFRACTIONt_it8412HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1075SEMIHARMONIC5
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_contact9938SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8412HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg11406HARMONIC21.22
X-RAY DIFFRACTIONt_omega_torsion3.04
X-RAY DIFFRACTIONt_other_torsion20.87
LS refinement shellResolution: 2.66→2.68 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.231 35 5.08 %
Rwork0.2247 654 -
all0.225 689 -
obs--87.7 %
Refinement TLS params.

T11: 0.304 Å2 / T22: -0.304 Å2 / T33: -0.304 Å2 / 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 °)T122)T132)T232)Origin x (Å)Origin y (Å)Origin z (Å)
11.78531.35720.49034.03460.31462.35320.10.4028-0.09350.42080.0922-0.3103-0.10360.1428-0.19210.1303-0.1087-0.005422.880111.66578.571
20.3202-0.78840.10716.7603-0.81743.89310.13680.12530.105-0.5442-0.0611-0.34550.03240.1633-0.0757-0.02020.02670.100922.051143.24984.6446
31.09650.43180.57875.26140.68623.85780.11750.2393-0.0797-0.0019-0.1776-0.1038-0.1714-0.19760.06010.152-0.00510.029767.47720.552635.2858
40-0.74430.24137.7823-0.38772.24340.17880.1281-0.0832-0.5442-0.1803-0.4150.04360.1060.00150.07290.0290.124167.7352.032131.3431
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|1 - A|333}A1 - 333
2X-RAY DIFFRACTION2{A|334 - A|1000 }A334 - 1000
3X-RAY DIFFRACTION3{B|1 - B|333}B1 - 333
4X-RAY DIFFRACTION4{B|334 - B|1000 }B334 - 1000

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