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- PDB-6tw0: Human CD73 (ecto 5'-nucleotidase) in complex with PSB12690 (an AO... -

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Basic information

Entry
Database: PDB / ID: 6tw0
TitleHuman CD73 (ecto 5'-nucleotidase) in complex with PSB12690 (an AOPCP derivative, compound 10 in publication) in the closed state
Components5'-nucleotidase
KeywordsHYDROLASE / nucleotide analog / eN / 5NT / complex
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; domain 2 / 5'-Nucleotidase, C-terminal domain / 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 / Metallo-dependent phosphatases ...5'-nucleotidase; domain 2 / 5'-Nucleotidase, C-terminal domain / 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 / Metallo-dependent phosphatases / Purple Acid Phosphatase; chain A, domain 2 / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Metallo-dependent phosphatase-like / 4-Layer Sandwich / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-NYZ / 5'-nucleotidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.5 Å
AuthorsPippel, J. / Strater, N.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)STR 477/13-2 Germany
CitationJournal: J.Med.Chem. / Year: 2020
Title: 2-Substituted alpha , beta-Methylene-ADP Derivatives: Potent Competitive Ecto-5'-nucleotidase (CD73) Inhibitors with Variable Binding Modes.
Authors: Bhattarai, S. / Pippel, J. / Scaletti, E. / Idris, R. / Freundlieb, M. / Rolshoven, G. / Renn, C. / Lee, S.Y. / Abdelrahman, A. / Zimmermann, H. / El-Tayeb, A. / Muller, C.E. / Strater, N.
History
DepositionJan 10, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 19, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,8324
Polymers59,2601
Non-polymers5723
Water27015
1
A: 5'-nucleotidase
hetero molecules

A: 5'-nucleotidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,6658
Polymers118,5212
Non-polymers1,1446
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_454-x-1,y,-z-1/21
Buried area2560 Å2
ΔGint-14 kcal/mol
Surface area40690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.451, 98.343, 233.750
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 59260.406 Da / Num. of mol.: 1
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.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-NYZ / [[(2~{R},3~{S},4~{R},5~{R})-5-(6-azanyl-2-oxidanylidene-3~{H}-purin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]methylphosphonic acid


Mass: 441.228 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H17N5O10P2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 15 / 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: 2.64 Å3/Da / Density % sol: 53.39 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: Reservoir: 5 % (w/v) polyethylene glycol 6000, 0.1 M NaMES pH 5.5. Drop: 1 microL crystallization buffer + 1 microL of 3 mg/mL protein in 10 mM Tris pH 8.0, 100 microM ZnCl2 and 1 mM of ...Details: Reservoir: 5 % (w/v) polyethylene glycol 6000, 0.1 M NaMES pH 5.5. Drop: 1 microL crystallization buffer + 1 microL of 3 mg/mL protein in 10 mM Tris pH 8.0, 100 microM ZnCl2 and 1 mM of compound. Cryo buffer: 25% PEG200, 0.1 M NaMES pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.5→48.12 Å / Num. obs: 22226 / % possible obs: 99.7 % / Redundancy: 7.3 % / Biso Wilson estimate: 66.87 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.349 / Rpim(I) all: 0.137 / Rrim(I) all: 0.375 / Net I/σ(I): 5.2 / Num. measured all: 161402 / Scaling rejects: 2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.5-2.67.15.0071755424640.1792.0075.4020.499.6
9.01-48.1260.04832555450.9980.0210.05327.799

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.2.8data scaling
BUSTER2.10.1refinement
PDB_EXTRACT3.25data extraction
BUSTER2.10.1phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4h2i

4h2i


Resolution: 2.5→48.12 Å / Cor.coef. Fo:Fc: 0.8874 / Cor.coef. Fo:Fc free: 0.8716 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.479 / SU Rfree Blow DPI: 0.279
RfactorNum. reflection% reflectionSelection details
Rfree0.2656 593 2.67 %RANDOM
Rwork0.2361 ---
obs0.2369 22178 99.68 %-
Displacement parametersBiso max: 202.17 Å2 / Biso mean: 96.91 Å2 / Biso min: 49.6 Å2
Baniso -1Baniso -2Baniso -3
1-17.2808 Å20 Å20 Å2
2---42.437 Å20 Å2
3---25.1562 Å2
Refine analyzeLuzzati coordinate error obs: 0.633 Å
Refinement stepCycle: final / Resolution: 2.5→48.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4040 0 44 15 4099
Biso mean--91.11 63.14 -
Num. residues----518
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1823SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes108HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1204HARMONIC5
X-RAY DIFFRACTIONt_it8193HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion535SEMIHARMONIC5
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_contact8605SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8193HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg14839HARMONIC21.12
X-RAY DIFFRACTIONt_omega_torsion3.9
X-RAY DIFFRACTIONt_other_torsion16.38
LS refinement shellResolution: 2.5→2.62 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2892 76 2.64 %
Rwork0.2928 2800 -
all0.2927 2876 -
obs--99.68 %
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)
13.2648-0.34691.87251.49420.58119.44510.16880.3182-0.1417-0.16830.0966-0.0777-0.62070.2928-0.2653-0.6174-0.00990.0343-0.6584-0.064-0.5868-21.195921.4657-16.0663
21.5579-0.07610.21722.17831.68498.4316-0.32170.047-0.0402-0.23670.7108-0.2588-1.16311.2838-0.3891-0.475-0.31680.1624-0.1028-0.1243-0.6863-18.326718.9249-47.9441
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|26 - 335}A26 - 335
2X-RAY DIFFRACTION2{A|336 - 549}A336 - 549

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