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- PDB-6s7h: Human CD73 (5'-nucleotidase) in complex with PSB12489 (an AOPCP d... -

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Basic information

Entry
Database: PDB / ID: 6s7h
TitleHuman CD73 (5'-nucleotidase) in complex with PSB12489 (an AOPCP derivative) in the closed state
Components5'-nucleotidase
KeywordsHYDROLASE / nucleotide analog / eN / 5NT / inhibitor / 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 / : / Purinergic signaling in leishmaniasis infection / calcium ion homeostasis / ATP metabolic process / negative regulation of inflammatory response / external side of plasma membrane / nucleotide binding / cell surface / extracellular exosome / zinc ion binding / 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-KYW / 5'-nucleotidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.85 Å
AuthorsPippel, J. / Strater, N.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationSTR 477/13-2 Germany
CitationJournal: Adv Ther / Year: 2019
Title: X-Ray Co-Crystal Structure Guides the Way to Subnanomolar Competitive Ecto-5'-Nucleotidase (CD73) Inhibitors for Cancer Immunotherapy
Authors: Bhattarai, S. / Pippel, J. / Meyer, A. / Freundlieb, M. / Schmies, C. / Abdelrahman, A. / Fiene, A. / Lee, S.Y. / Zimmermann, H. / El-Tayeb, A. / Yegutkin, G.G. / Strater, N. / Muller, C.E.
History
DepositionJul 4, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 22, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 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)60,0255
Polymers59,2901
Non-polymers7354
Water5,549308
1
A: 5'-nucleotidase
hetero molecules

A: 5'-nucleotidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,05010
Polymers118,5812
Non-polymers1,4698
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_454-x-1,y,-z-1/21
Buried area2700 Å2
ΔGint-36 kcal/mol
Surface area40360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.830, 95.800, 233.590
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-998-

HOH

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Components

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


Mass: 59290.430 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-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-KYW / (N6,N6)-methyl,benzyl-C2-chloro-(alpha,beta)-methylene-ADP


Mass: 563.822 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24ClN5O9P2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 308 / 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: 2.54 Å3/Da / Density % sol: 51.57 %
Crystal growTemperature: 292.15 K / Method: vapor diffusion, hanging drop
Details: Crystallization buffer: 5 % (w/v) polyethylene glycol 6000, 0.1 M citric acid pH 5.0-6.0. Crystallization drop:1 uL crystallization buffer + 1 uL of 3 mg/mL protein in 10 mM Tris pH 8.0, 100 ...Details: Crystallization buffer: 5 % (w/v) polyethylene glycol 6000, 0.1 M citric acid pH 5.0-6.0. Crystallization drop:1 uL crystallization buffer + 1 uL of 3 mg/mL protein in 10 mM Tris pH 8.0, 100 uM ZnCl2, 1 mM Inhibitor. Cryobuffer: 25 % (v/v) polyethylene glycol 200, 0.1 MES 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: 0.918409 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 15, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918409 Å / Relative weight: 1
ReflectionResolution: 1.85→29.2 Å / Num. obs: 49414 / % possible obs: 94.8 % / Redundancy: 6.8 % / Biso Wilson estimate: 35.27 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.113 / Rpim(I) all: 0.047 / Rrim(I) all: 0.122 / Net I/σ(I): 12.7 / Num. measured all: 334547 / Scaling rejects: 31
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.85-1.8963.640.631870.2851.6023.98699.8
9.06-29.26.40.01950010.0080.02197.4

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Processing

Software
NameVersionClassification
XDSNovember 3, 2014data reduction
Aimless0.2.8data scaling
BUSTER2.10.1refinement
PDB_EXTRACT3.25data extraction
BUSTER2.10.1refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4h2i

4h2i


Resolution: 1.85→29.2 Å / Cor.coef. Fo:Fc: 0.9479 / Cor.coef. Fo:Fc free: 0.9438 / SU R Cruickshank DPI: 0.183 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.127 / SU Rfree Blow DPI: 0.111 / SU Rfree Cruickshank DPI: 0.112
RfactorNum. reflection% reflectionSelection details
Rfree0.1989 1271 2.58 %RANDOM
Rwork0.1807 ---
obs0.1812 49340 94.75 %-
Displacement parametersBiso max: 211.48 Å2 / Biso mean: 56.28 Å2 / Biso min: 22.92 Å2
Baniso -1Baniso -2Baniso -3
1-0.836 Å20 Å20 Å2
2---10.9972 Å20 Å2
3---10.1612 Å2
Refine analyzeLuzzati coordinate error obs: 0.339 Å
Refinement stepCycle: final / Resolution: 1.85→29.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4041 0 60 308 4409
Biso mean--48.08 52.65 -
Num. residues----519
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1876SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes107HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1233HARMONIC5
X-RAY DIFFRACTIONt_it8307HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion543SEMIHARMONIC5
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_contact9279SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8307HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg15048HARMONIC21.13
X-RAY DIFFRACTIONt_omega_torsion4.06
X-RAY DIFFRACTIONt_other_torsion13.17
LS refinement shellResolution: 1.85→1.9 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.235 113 2.97 %
Rwork0.2248 3687 -
all0.2251 3800 -
obs--94.75 %
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)
11.2598-0.63850.51411.4142-0.97365.9530.09730.15310.04780.1096-0.057-0.0552-0.9274-0.0015-0.0402-0.02080.0320.0355-0.1656-0.034-0.1446-21.18421.4391-16.072
21.2015-0.0830.35680.96721.19098.3667-0.11520.210.0259-0.07490.3252-0.1195-0.81620.7427-0.21-0.2579-0.04590.0907-0.0956-0.0533-0.3347-18.335918.9203-47.9602
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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