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- PDB-7qgl: Human CD73 (ecto 5'-nucleotidase) in complex with MRS4602 (a 3-me... -

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Basic information

Entry
Database: PDB / ID: 7qgl
TitleHuman CD73 (ecto 5'-nucleotidase) in complex with MRS4602 (a 3-methyl-CMPCP derivative, compound 21 in paper) in the open state
Components5'-nucleotidase
KeywordsHYDROLASE / en / e5nt / ecto-nucleotidase / inhibitor
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 / leukocyte cell-cell adhesion / DNA metabolic process / 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 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-BW0 / 5'-nucleotidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.5 Å
AuthorsStrater, N.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)358304989 Germany
CitationJournal: J.Med.Chem. / Year: 2022
Title: Structure-Activity Relationship of 3-Methylcytidine-5'-alpha , beta-methylenediphosphates as CD73 Inhibitors.
Authors: Scortichini, M. / Idris, R.M. / Moschutz, S. / Keim, A. / Salmaso, V. / Dobelmann, C. / Oliva, P. / Losenkova, K. / Irjala, H. / Vaittinen, S. / Sandholm, J. / Yegutkin, G.G. / Strater, N. / ...Authors: Scortichini, M. / Idris, R.M. / Moschutz, S. / Keim, A. / Salmaso, V. / Dobelmann, C. / Oliva, P. / Losenkova, K. / Irjala, H. / Vaittinen, S. / Sandholm, J. / Yegutkin, G.G. / Strater, N. / Junker, A. / Muller, C.E. / Jacobson, K.A.
History
DepositionDec 8, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 16, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 23, 2022Group: 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 1.2Jan 31, 2024Group: Author supporting evidence / Data collection ...Author supporting evidence / Data collection / Refinement description / Structure summary
Category: audit_author / chem_comp_atom ...audit_author / chem_comp_atom / chem_comp_bond / pdbx_audit_support / pdbx_initial_refinement_model
Item: _audit_author.name / _pdbx_audit_support.country ..._audit_author.name / _pdbx_audit_support.country / _pdbx_audit_support.funding_organization / _pdbx_audit_support.grant_number

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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)62,0679
Polymers60,3631
Non-polymers1,7038
Water11,746652
1
A: 5'-nucleotidase
hetero molecules

A: 5'-nucleotidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,13318
Polymers120,7272
Non-polymers3,40716
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
Buried area6290 Å2
ΔGint-190 kcal/mol
Surface area39060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.856, 129.841, 65.797
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, 1 molecules A

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


Mass: 60363.316 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: Homo sapiens (human) / References: UniProt: P21589, 5'-nucleotidase

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Non-polymers , 5 types, 660 molecules

#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-BW0 / [[(2~{R},3~{S},4~{R},5~{R})-5-[(4~{E})-4-[(4-methoxycarbonylphenyl)methoxyimino]-3-methyl-2-oxidanylidene-pyrimidin-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]methylphosphonic acid


Mass: 579.388 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H27N3O13P2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400 / Polyethylene glycol


Mass: 238.278 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 652 / 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 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 10 mM MRS4602, 100 microM ZnCl2, 8 % PEG 6.000, 0.1 M MES pH 6.2, 20 % PEG200

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU HyPix-6000HE / Detector: PIXEL / Date: Sep 16, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.5→21.63 Å / Num. obs: 91996 / % possible obs: 99.6 % / Redundancy: 3.9 % / Biso Wilson estimate: 12.3 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.031 / Rrim(I) all: 0.065 / Net I/σ(I): 14.8 / Num. measured all: 362347 / Scaling rejects: 217
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
1.5-1.532.80.441251944820.7430.310.5412.399.1
8.22-21.636.40.02538876110.9990.010.02752.393.8

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
BUSTER2.10.4 (20-OCT-2021)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6tve

6tve


Resolution: 1.5→21.63 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.956 / SU R Cruickshank DPI: 0.062 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.067 / SU Rfree Blow DPI: 0.064 / SU Rfree Cruickshank DPI: 0.061
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.1745 4595 5 %RANDOM
Rwork0.1577 ---
obs0.1585 91936 99.6 %-
Displacement parametersBiso max: 116.04 Å2 / Biso mean: 14.73 Å2 / Biso min: 4.53 Å2
Baniso -1Baniso -2Baniso -3
1-0.5053 Å20 Å20 Å2
2---1.2934 Å20 Å2
3---0.7881 Å2
Refine analyzeLuzzati coordinate error obs: 0.16 Å
Refinement stepCycle: final / Resolution: 1.5→21.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4081 0 93 652 4826
Biso mean--21.51 31.42 -
Num. residues----523
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1621SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes801HARMONIC5
X-RAY DIFFRACTIONt_it4471HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion570SEMIHARMONIC5
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_contact5053SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4498HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg6148HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion4.56
X-RAY DIFFRACTIONt_other_torsion14.15
LS refinement shellResolution: 1.5→1.51 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2323 103 5.6 %
Rwork0.2228 1736 -
all0.2234 1839 -
obs--98.82 %
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)
10.29020.04080.00210.38880.05960.23290.01840.00010.0217-0.0252-0.01570.00140.01120.0033-0.0026-0.0012-0.0012-0.0046-0.01690.0023-0.015223.174833.68913.4513
20.3024-0.04230.1310.3944-0.02790.1784-0.0276-0.0228-0.0064-0.00710.01610.0115-0.01750.00930.0115-0.00390.01140.0011-0.0166-0.0011-0.011425.118410.463335.3059
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|27 - A|333 A|601 - A|603}A27 - 333
2X-RAY DIFFRACTION1{A|27 - A|333 A|601 - A|603}A601 - 603
3X-RAY DIFFRACTION2{A|334 - A|549}A334 - 549

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