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- PDB-6z9b: Human Ecto-5'-nucleotidase (CD73) in complex with AOPCP derivativ... -

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Basic information

Entry
Database: PDB / ID: 6z9b
TitleHuman Ecto-5'-nucleotidase (CD73) in complex with AOPCP derivative A830 (compound 16 in publication) in the closed form (crystal form III)
Components5'-nucleotidase
KeywordsHYDROLASE / zinc enzyme / nucleotide analog / inhibitor / Arcus Biosciences
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 / GMP 5'-nucleotidase activity ...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 / GMP 5'-nucleotidase activity / IMP-specific 5'-nucleotidase / IMP 5'-nucleotidase activity / AMP catabolic process / Nicotinate metabolism / Purine catabolism / XMP 5'-nucleosidase activity / 5'-nucleotidase / 5'-nucleotidase activity / leukocyte cell-cell adhesion / DNA metabolic process / response to ATP / : / 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 / zinc ion binding / extracellular exosome / nucleoplasm / identical protein binding / membrane / 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-QCQ / 5'-nucleotidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.17 Å
Model detailsThe compound is a competitive non-nucleotide inhibitor binding to the active site
AuthorsStrater, N. / Scaletti, E.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of AB680: A Potent and Selective Inhibitor of CD73.
Authors: Lawson, K.V. / Kalisiak, J. / Lindsey, E.A. / Newcomb, E.T. / Leleti, M.R. / Debien, L. / Rosen, B.R. / Miles, D.H. / Sharif, E.U. / Jeffrey, J.L. / Tan, J.B.L. / Chen, A. / Zhao, S. / Xu, G. ...Authors: Lawson, K.V. / Kalisiak, J. / Lindsey, E.A. / Newcomb, E.T. / Leleti, M.R. / Debien, L. / Rosen, B.R. / Miles, D.H. / Sharif, E.U. / Jeffrey, J.L. / Tan, J.B.L. / Chen, A. / Zhao, S. / Xu, G. / Fu, L. / Jin, L. / Park, T.W. / Berry, W. / Moschutz, S. / Scaletti, E. / Strater, N. / Walker, N.P. / Young, S.W. / Walters, M.J. / Schindler, U. / Powers, J.P.
History
DepositionJun 3, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 22, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 4, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 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)59,9835
Polymers59,2601
Non-polymers7234
Water5,134285
1
A: 5'-nucleotidase
hetero molecules

A: 5'-nucleotidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,96610
Polymers118,5212
Non-polymers1,4458
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_454-x-1,y,-z-1/21
Buried area2770 Å2
ΔGint-32 kcal/mol
Surface area40190 Å2
Unit cell
Length a, b, c (Å)53.240, 96.450, 235.170
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
Details: CD73 Construct 4.0 for E. coli expression and refolding
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-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-QCQ / [[(2~{R},3~{R},4~{S},5~{R})-5-[2-chloranyl-6-[(phenylmethyl)amino]purin-9-yl]-4-fluoranyl-3-oxidanyl-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]methylphosphonic acid


Mass: 551.787 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21ClFN5O8P2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 285 / 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: 2.55 Å3/Da / Density % sol: 51.71 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: CD73 at 7 mg/mL was incubated on ice for one hour with 1mM of the inhibitor and 0.1 mM ZnCl2. 1 uL of protein was mixed with 1 uL of 11-14% PEG6000 and 100 mM sodium citrate pH 5.4-5.6. For ...Details: CD73 at 7 mg/mL was incubated on ice for one hour with 1mM of the inhibitor and 0.1 mM ZnCl2. 1 uL of protein was mixed with 1 uL of 11-14% PEG6000 and 100 mM sodium citrate pH 5.4-5.6. For cryoprotection glycerol was added to a final concentration of 15 % to the reservoir buffer.

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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 24, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.17→48.23 Å / Num. obs: 32496 / % possible obs: 99.2 % / Redundancy: 6.425 % / Biso Wilson estimate: 32.78 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.223 / Rrim(I) all: 0.243 / Χ2: 0.803 / Net I/σ(I): 8.61
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
2.17-2.36.0380.8361.830625526050720.8370.91596.4
2.3-2.466.8030.6972.5233061487148600.8980.75599.8
2.46-2.656.380.5343.2329120458545640.9380.58299.5
2.65-2.916.6780.3664.9528229423242270.970.39899.9
2.91-3.256.1930.2657.1423615383238130.9810.2999.5
3.25-3.756.5060.18112.9722096340333960.9880.19799.8
3.75-4.586.4870.12920.8818922292129170.990.1499.9
4.58-6.456.4740.10722.4614742228022770.9950.11699.9
6.45-48.236.1210.07228.98319136913590.9980.07999.3

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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: pdbid 4H2I

4h2i


Resolution: 2.17→48.23 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.881 / SU R Cruickshank DPI: 0.245 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.26 / SU Rfree Blow DPI: 0.213 / SU Rfree Cruickshank DPI: 0.21
RfactorNum. reflection% reflectionSelection details
Rfree0.263 1625 5 %RANDOM
Rwork0.208 ---
obs0.21 32496 99.2 %-
Displacement parametersBiso max: 131.03 Å2 / Biso mean: 42.75 Å2 / Biso min: 18.89 Å2
Baniso -1Baniso -2Baniso -3
1-2.532 Å20 Å20 Å2
2---13.9648 Å20 Å2
3---11.4328 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.17→48.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4064 0 38 285 4387
Biso mean--34.52 41.82 -
Num. residues----521
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1464SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes730HARMONIC5
X-RAY DIFFRACTIONt_it4198HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion536SEMIHARMONIC5
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_contact4960SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4198HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5693HARMONIC21.16
X-RAY DIFFRACTIONt_omega_torsion3.48
X-RAY DIFFRACTIONt_other_torsion20.13
LS refinement shellResolution: 2.17→2.18 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2175 32 4.92 %
Rwork0.2446 618 -
all0.2434 650 -
obs--86.41 %
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)
11.0949-0.28470.09440.86720.0032.06520.03830.18170.01470.0332-0.06140.005-0.21270.0380.0231-0.1280.01060.00150.1221-0.0266-0.2224-20.97421.1955-16.2391
20.850.05370.43720.81650.85885.9305-0.13720.12840.00950.03590.2412-0.098-0.12190.5442-0.104-0.29560.00170.02640.2298-0.0151-0.304-17.955218.9849-48.4863
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|1 - A|333 A|601 - A|603}A1 - 333
2X-RAY DIFFRACTION1{A|1 - A|333 A|601 - A|603}A601 - 603
3X-RAY DIFFRACTION2{A|334 - A|549}A334 - 549

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