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- PDB-6xug: Human Ecto-5'-nucleotidase (CD73) in complex with A2410 (compound... -

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Entry
Database: PDB / ID: 6xug
TitleHuman Ecto-5'-nucleotidase (CD73) in complex with A2410 (compound 53 in publication) in the closed form in crystal form IV
Components5'-nucleotidase
KeywordsHYDROLASE / non-nucleotide 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 / 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-O1Q / PHOSPHATE ION / 5'-nucleotidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.09 Å
Model detailsThe compound is a competitive non-nucleotide inhibitor binding to the active site
AuthorsStrater, N.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73.
Authors: Beatty, J.W. / Lindsey, E.A. / Thomas-Tran, R. / Debien, L. / Mandal, D. / Jeffrey, J.L. / Tran, A.T. / Fournier, J. / Jacob, S.D. / Yan, X. / Drew, S.L. / Ginn, E. / Chen, A. / Pham, A.T. / ...Authors: Beatty, J.W. / Lindsey, E.A. / Thomas-Tran, R. / Debien, L. / Mandal, D. / Jeffrey, J.L. / Tran, A.T. / Fournier, J. / Jacob, S.D. / Yan, X. / Drew, S.L. / Ginn, E. / Chen, A. / Pham, A.T. / Zhao, S. / Jin, L. / Young, S.W. / Walker, N.P. / Leleti, M.R. / Moschutz, S. / Strater, N. / Powers, J.P. / Lawson, K.V.
History
DepositionJan 19, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: 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 2.0Sep 23, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Other / Polymer sequence / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / atom_sites / cell / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_distant_solvent_atoms / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_refine_tls / pdbx_refine_tls_group / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_conn_angle / pdbx_struct_oper_list / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / pdbx_validate_torsion / refine / refine_hist / refine_ls_restr / refine_ls_shell / struct_conf / struct_conn / struct_mon_prot_cis / struct_ref_seq / struct_ref_seq_dif / struct_sheet_range / struct_site / struct_site_gen
Item: _atom_sites.fract_transf_matrix[3][3] / _cell.length_a ..._atom_sites.fract_transf_matrix[3][3] / _cell.length_a / _cell.length_b / _cell.length_c / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.pdbx_end_seq_num / _pdbx_entity_nonpoly.comp_id / _pdbx_entity_nonpoly.name / _pdbx_refine_tls.L[1][1] / _pdbx_refine_tls.L[1][2] / _pdbx_refine_tls.L[1][3] / _pdbx_refine_tls.L[2][2] / _pdbx_refine_tls.L[2][3] / _pdbx_refine_tls.L[3][3] / _pdbx_refine_tls.S[1][1] / _pdbx_refine_tls.S[1][2] / _pdbx_refine_tls.S[1][3] / _pdbx_refine_tls.S[2][1] / _pdbx_refine_tls.S[2][2] / _pdbx_refine_tls.S[2][3] / _pdbx_refine_tls.S[3][1] / _pdbx_refine_tls.S[3][2] / _pdbx_refine_tls.S[3][3] / _pdbx_refine_tls.T[1][1] / _pdbx_refine_tls.T[1][2] / _pdbx_refine_tls.T[1][3] / _pdbx_refine_tls.T[2][2] / _pdbx_refine_tls.T[2][3] / _pdbx_refine_tls.T[3][3] / _pdbx_refine_tls.origin_x / _pdbx_refine_tls.origin_y / _pdbx_refine_tls.origin_z / _pdbx_struct_assembly_prop.value / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _pdbx_struct_sheet_hbond.range_1_auth_comp_id / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_1_label_comp_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_comp_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_label_comp_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _refine.B_iso_max / _refine.B_iso_mean / _refine.aniso_B[1][1] / _refine.aniso_B[2][2] / _refine.aniso_B[3][3] / _refine.correlation_coeff_Fo_to_Fc_free / _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.ls_d_res_low / _refine.ls_number_reflns_obs / _refine.pdbx_overall_SU_R_Blow_DPI / _refine.pdbx_overall_SU_R_free_Cruickshank_DPI / _refine_hist.d_res_low / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_B_iso_mean_ligand / _refine_hist.pdbx_B_iso_mean_solvent / _refine_hist.pdbx_number_atoms_protein / _refine_hist.pdbx_number_residues_total / _refine_ls_restr.dev_ideal / _refine_ls_restr.number / _refine_ls_shell.R_factor_R_free / _refine_ls_shell.R_factor_R_work / _refine_ls_shell.R_factor_all / _refine_ls_shell.percent_reflns_obs / _struct_conf.beg_label_seq_id / _struct_conf.end_auth_comp_id / _struct_conf.end_auth_seq_id / _struct_conf.end_label_comp_id / _struct_conf.end_label_seq_id / _struct_conf.pdbx_PDB_helix_class / _struct_conf.pdbx_PDB_helix_length / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_mon_prot_cis.label_seq_id / _struct_mon_prot_cis.pdbx_label_seq_id_2 / _struct_mon_prot_cis.pdbx_omega_angle / _struct_ref_seq.seq_align_beg / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_label_seq_id
Description: Model orientation/position
Details: The two chains have been placed in the asymmetric unit such that they form the physiological dimer
Provider: author / Type: Coordinate replacement
Revision 2.1Jan 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
B: 5'-nucleotidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,27212
Polymers118,8892
Non-polymers1,38310
Water15,223845
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3530 Å2
ΔGint-212 kcal/mol
Surface area38450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.750, 230.010, 54.270
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 59444.477 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NT5E, NT5, NTE / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P21589, 5'-nucleotidase

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Non-polymers , 5 types, 855 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-O1Q / 4-chloranyl-1-(1~{H}-indazol-6-yl)-6-[2-(3-methylphenyl)pyrazol-3-yl]benzotriazole


Mass: 425.873 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H16ClN7 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 845 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.37 Å3/Da / Density % sol: 48.11 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: Reservoir: 9 % PEG 6000, 0.1 M MES pH 5.8. Drop: 1 micro-L crystallization buffer +1 micro-L of 3 mg/mL CD73 in 10 mM Tris pH 8.0, 10 micro-M ZnCl2; 200 micro-M NaH2PO4, 3 % DMSO, compound: ...Details: Reservoir: 9 % PEG 6000, 0.1 M MES pH 5.8. Drop: 1 micro-L crystallization buffer +1 micro-L of 3 mg/mL CD73 in 10 mM Tris pH 8.0, 10 micro-M ZnCl2; 200 micro-M NaH2PO4, 3 % DMSO, compound: saturated solution. Cryo: 20% PEG200 in crystallization drop

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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: Jan 24, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.09→86.81 Å / Num. obs: 70479 / % possible obs: 99.7 % / Redundancy: 9.1 % / Biso Wilson estimate: 25.56 Å2 / Rpim(I) all: 0.091 / Rrim(I) all: 0.281 / Net I/σ(I): 5.3 / Num. measured all: 643925
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
2.09-2.127.41.82466133420.3350.94697
5.67-86.898.411.63218338360.0340.1100

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
xia2data scaling
PDB_EXTRACT3.25data extraction
DIALSdata reduction
autoBUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4H2I

4h2i


Resolution: 2.09→72.67 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.926 / SU R Cruickshank DPI: 0.2 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.219 / SU Rfree Blow DPI: 0.182 / SU Rfree Cruickshank DPI: 0.177
RfactorNum. reflection% reflectionSelection details
Rfree0.237 3452 4.9 %RANDOM
Rwork0.188 ---
obs0.19 70395 99.6 %-
Displacement parametersBiso max: 147.44 Å2 / Biso mean: 40.31 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-1.9 Å20 Å20 Å2
2---1.7005 Å20 Å2
3----0.1995 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.09→72.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8006 0 78 845 8929
Biso mean--23.54 39.68 -
Num. residues----1029
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2888SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1519HARMONIC5
X-RAY DIFFRACTIONt_it8332HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1058SEMIHARMONIC5
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_contact10493SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8332HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg11329HARMONIC21.16
X-RAY DIFFRACTIONt_omega_torsion3.59
X-RAY DIFFRACTIONt_other_torsion17.46
LS refinement shellResolution: 2.09→2.1 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2668 59 4.19 %
Rwork0.2522 1349 -
all0.2529 1408 -
obs--94.21 %
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)
11.21710.0627-0.15322.71770.03271.63460.02150.1133-0.0053-0.1347-0.0317-0.0986-0.0533-0.10650.01020.27470.00930.0178-0.2508-0.011-0.20423.223311.71428.1854
20.45880.0820.08223.2320.12431.46770.04420.09520.1205-0.10940.0419-0.2074-0.3205-0.0743-0.08610.41680.05170.0568-0.34480.0505-0.256323.151842.40915.2574
31.3868-0.4904-0.23173.69330.27861.5986-0.0367-0.06810.095-0.06260.0161-0.05510.02260.07280.02050.28310.0089-0.0087-0.2978-0.0034-0.227421.984994.224219.2376
40.0359-0.0720.33654.21080.0581.052-0.0575-0.0405-0.10570.0470.0782-0.09590.25390.006-0.02080.42580.03560.0619-0.3380.0537-0.22823.011763.74322.3442
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|1 - A|333 A|601 - A|604 }A1 - 333
2X-RAY DIFFRACTION1{ A|1 - A|333 A|601 - A|604 }A601 - 604
3X-RAY DIFFRACTION2{ A|334 - A|549 }A334 - 549
4X-RAY DIFFRACTION3{ B|1 - B|333 B|601 - B|604 }B1 - 333
5X-RAY DIFFRACTION3{ B|1 - B|333 B|601 - B|604 }B601 - 604
6X-RAY DIFFRACTION4{ B|334 - B|549 }B334 - 549

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