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- PDB-6twf: Human CD73 (ecto 5'-nucleotidase) in complex with PSB12604 (an AO... -

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Basic information

Entry
Database: PDB / ID: 6twf
TitleHuman CD73 (ecto 5'-nucleotidase) in complex with PSB12604 (an AOPCP derivative, compound 21 in publication) in the closed state
Components5'-nucleotidase
KeywordsHYDROLASE / nucleotide analog / eN / 5NT / complex
Function / homology
Function and homology information


thymidylate 5'-phosphatase / : / ADP catabolic process / 5'-deoxynucleotidase / 5'-deoxynucleotidase activity / 7-methylguanosine nucleotidase / adenosine biosynthetic process / inhibition of non-skeletal tissue mineralization / Pyrimidine catabolism / AMP catabolic process ...thymidylate 5'-phosphatase / : / ADP catabolic process / 5'-deoxynucleotidase / 5'-deoxynucleotidase activity / 7-methylguanosine nucleotidase / adenosine biosynthetic process / inhibition of non-skeletal tissue mineralization / Pyrimidine catabolism / AMP catabolic process / : / IMP-specific 5'-nucleotidase / : / Nicotinate metabolism / Purine catabolism / 5'-nucleotidase / 5'-nucleotidase activity / leukocyte cell-cell adhesion / DNA metabolic process / response to ATP / Purinergic signaling in leishmaniasis infection / ATP metabolic process / calcium ion homeostasis / 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; domain 2 / 5'-Nucleotidase, C-terminal domain / 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 signature 1. / 5'-nucleotidase; domain 2 / 5'-Nucleotidase, C-terminal domain / 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-O05 / 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 13, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 19, 2020Provider: repository / Type: Initial release
Revision 2.0Apr 8, 2020Group: Database references / Non-polymer description / Category: chem_comp / citation / citation_author
Item: _chem_comp.formula / _citation.journal_volume ..._chem_comp.formula / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 2.1Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Revision 2.2Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)59,9425
Polymers59,2601
Non-polymers6814
Water724
1
A: 5'-nucleotidase
hetero molecules

A: 5'-nucleotidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,88310
Polymers118,5212
Non-polymers1,3638
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_454-x-1,y,-z-1/21
Buried area2620 Å2
ΔGint-34 kcal/mol
Surface area40170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.453, 97.217, 234.369
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-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-O05 / [[(2~{R},3~{S},4~{R},5~{R})-5-(6-azanyl-2-piperazin-4-ium-1-yl-purin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]methylphosphonic acid


Mass: 510.356 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H26N7O9P2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.62 Å3/Da / Density % sol: 52.98 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: Reservoir: 5-8 % (w/v) polyethylene glycol 6000, 0.1 M NaMES pH 5.5-6.0. 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 ...Details: Reservoir: 5-8 % (w/v) polyethylene glycol 6000, 0.1 M NaMES pH 5.5-6.0. 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: 25% PEG200, 0.1 M Na-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: 0.91841 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 28, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 2.5→47.6 Å / Num. obs: 21964 / % possible obs: 99.6 % / Redundancy: 5.4 % / Biso Wilson estimate: 57.26 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.201 / Rpim(I) all: 0.094 / Rrim(I) all: 0.223 / Net I/σ(I): 7 / Num. measured all: 118507
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
2.5-2.65.33.131286124350.2461.4613.4650.799.8
9.01-47.64.50.03222985130.9990.0160.03638.997.4

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Processing

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

4h2i


Resolution: 2.5→47.6 Å / Cor.coef. Fo:Fc: 0.9093 / Cor.coef. Fo:Fc free: 0.8957 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.504 / SU Rfree Blow DPI: 0.286
RfactorNum. reflection% reflectionSelection details
Rfree0.2618 565 2.68 %RANDOM
Rwork0.2199 ---
obs0.221 21045 95.44 %-
Displacement parametersBiso max: 212.61 Å2 / Biso mean: 108.59 Å2 / Biso min: 58.4 Å2
Baniso -1Baniso -2Baniso -3
1-17.7776 Å20 Å20 Å2
2---46.4859 Å20 Å2
3---28.7083 Å2
Refine analyzeLuzzati coordinate error obs: 0.613 Å
Refinement stepCycle: final / Resolution: 2.5→47.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4062 0 58 4 4124
Biso mean--120.31 79.51 -
Num. residues----522
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1836SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes108HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1221HARMONIC5
X-RAY DIFFRACTIONt_it8264HARMONIC20
X-RAY DIFFRACTIONt_nbd5SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion537SEMIHARMONIC5
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_contact8784SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8264HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg14981HARMONIC21.24
X-RAY DIFFRACTIONt_omega_torsion4.04
X-RAY DIFFRACTIONt_other_torsion16.89
LS refinement shellResolution: 2.5→2.62 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2749 61 2.49 %
Rwork0.2349 2387 -
all0.2359 2448 -
obs--95.44 %
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)
13.7272-0.86932.93241.9123-0.398410.22860.25520.6935-0.2533-0.2428-0.006-0.111-0.43710.6967-0.2492-0.60470.02590.0307-0.3765-0.143-0.7264-21.18421.4391-16.072
22.539-0.20220.17062.19732.34799.9803-0.35790.0095-0.0622-0.14690.8667-0.3498-1.43451.5544-0.5088-0.5172-0.32110.17010.027-0.184-0.8033-18.335918.9203-47.9602
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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