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- PDB-8aup: Structure of hARG1 with a novel inhibitor. -

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Basic information

Entry
Database: PDB / ID: 8aup
TitleStructure of hARG1 with a novel inhibitor.
ComponentsArginase-1
KeywordsHYDROLASE / protein-inhibitor complex
Function / homology
Function and homology information


positive regulation of neutrophil mediated killing of fungus / Urea cycle / negative regulation of T-helper 2 cell cytokine production / arginase / arginase activity / arginine catabolic process to ornithine / urea cycle / negative regulation of type II interferon-mediated signaling pathway / defense response to protozoan / negative regulation of activated T cell proliferation ...positive regulation of neutrophil mediated killing of fungus / Urea cycle / negative regulation of T-helper 2 cell cytokine production / arginase / arginase activity / arginine catabolic process to ornithine / urea cycle / negative regulation of type II interferon-mediated signaling pathway / defense response to protozoan / negative regulation of activated T cell proliferation / arginine catabolic process / negative regulation of T cell proliferation / specific granule lumen / azurophil granule lumen / manganese ion binding / adaptive immune response / innate immune response / Neutrophil degranulation / extracellular space / extracellular region / nucleus / cytoplasm / cytosol
Similarity search - Function
Arginase / Ureohydrolase, manganese-binding site / Arginase family signature. / Ureohydrolase / Arginase family / Arginase family profile. / Ureohydrolase domain superfamily
Similarity search - Domain/homology
HEXANE-1,6-DIOL / : / Chem-O93 / Arginase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 Å
AuthorsNapiorkowska-Gromadzka, A. / Nowak, E. / Nowotny, M.
Funding support Poland, European Union, 2items
OrganizationGrant numberCountry
National Center for Research and Development (Poland)STRATEGMED2/265503/3/NCBR/15 Poland
European Union (EU)POIR.01.01.01-00-0415/17European Union
CitationJournal: Mol.Cancer Ther. / Year: 2023
Title: Arginase 1/2 Inhibitor OATD-02: From Discovery to First-in-man Setup in Cancer Immunotherapy.
Authors: Borek, B. / Nowicka, J. / Gzik, A. / Dziegielewski, M. / Jedrzejczak, K. / Brzezinska, J. / Grzybowski, M. / Stanczak, P. / Pomper, P. / Zagozdzon, A. / Rejczak, T. / Matyszewski, K. / ...Authors: Borek, B. / Nowicka, J. / Gzik, A. / Dziegielewski, M. / Jedrzejczak, K. / Brzezinska, J. / Grzybowski, M. / Stanczak, P. / Pomper, P. / Zagozdzon, A. / Rejczak, T. / Matyszewski, K. / Golebiowski, A. / Olczak, J. / Lisiecki, K. / Tyszkiewicz, M. / Kania, M. / Piasecka, S. / Cabaj, A. / Dera, P. / Mulewski, K. / Chrzanowski, J. / Kusmirek, D. / Sobolewska, E. / Magdycz, M. / Mucha, L. / Masnyk, M. / Golab, J. / Nowotny, M. / Nowak, E. / Napiorkowska-Gromadzka, A. / Pikul, S. / Jazwiec, R. / Dzwonek, K. / Dobrzanski, P. / Meyring, M. / Skowronek, K. / Iwanowski, P. / Zaslona, Z. / Blaszczyk, R.
History
DepositionAug 25, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2023Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 19, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Arginase-1
B: Arginase-1
C: Arginase-1
D: Arginase-1
E: Arginase-1
F: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)211,31626
Polymers208,6796
Non-polymers2,63720
Water15,097838
1
A: Arginase-1
hetero molecules

D: Arginase-1
hetero molecules

E: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,65813
Polymers104,3403
Non-polymers1,31810
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_445x-1,y-1,z1
crystal symmetry operation1_545x,y-1,z1
Buried area5460 Å2
ΔGint-13 kcal/mol
Surface area32530 Å2
MethodPISA
2
B: Arginase-1
C: Arginase-1
F: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,65813
Polymers104,3403
Non-polymers1,31810
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5750 Å2
ΔGint-26 kcal/mol
Surface area32060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.360, 52.750, 283.600
Angle α, β, γ (deg.)90.000, 90.650, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 6 molecules ABCDEF

#1: Protein
Arginase-1 / Liver-type arginase / Type I arginase


Mass: 34779.879 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Details: electron density not observed for D316 / Source: (gene. exp.) Homo sapiens (human) / Gene: ARG1 / Production host: Escherichia coli (E. coli) / References: UniProt: P05089, arginase

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Non-polymers , 5 types, 858 molecules

#2: Chemical
ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Mn
#3: Chemical
ChemComp-O93 / 2-[(1~{R},3~{R},4~{S})-3-azanyl-3-carboxy-4-[(dimethylamino)methyl]cyclohexyl]ethyl-$l^{3}-oxidanyl-bis(oxidanyl)boron


Mass: 290.164 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C12H27BN2O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-HEZ / HEXANE-1,6-DIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2
#5: Chemical ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 838 / 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: 2.41 Å3/Da / Density % sol: 49.05 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: MPD, PEG 1000, PEG 3350, HEPES-Na, MOPS, hexanediol, butanol, propandiol, propanol, butandiol, propandiol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 20, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918 Å / Relative weight: 1
ReflectionResolution: 2.17→49.11 Å / Num. obs: 105864 / % possible obs: 99.5 % / Redundancy: 3.75 % / Biso Wilson estimate: 28.84 Å2 / CC1/2: 0.99 / Net I/σ(I): 6.1
Reflection shellResolution: 2.17→2.3 Å / Num. unique obs: 16919 / CC1/2: 0.62

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PHENIX1.19.2_4158refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GWD

4gwd


Resolution: 2.17→49.11 Å / SU ML: 0.3065 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.9835
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2401 2101 1.99 %
Rwork0.207 103740 -
obs0.2076 105841 99.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.55 Å2
Refinement stepCycle: LAST / Resolution: 2.17→49.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14309 0 148 838 15295
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002514756
X-RAY DIFFRACTIONf_angle_d0.598920070
X-RAY DIFFRACTIONf_chiral_restr0.0452323
X-RAY DIFFRACTIONf_plane_restr0.00462575
X-RAY DIFFRACTIONf_dihedral_angle_d10.36972076
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.17-2.220.3951380.35536824X-RAY DIFFRACTION99.5
2.22-2.280.34681380.31096816X-RAY DIFFRACTION98.68
2.28-2.340.32781390.29126846X-RAY DIFFRACTION99.6
2.34-2.410.28671420.28136994X-RAY DIFFRACTION99.9
2.41-2.480.29171380.27686816X-RAY DIFFRACTION99.77
2.48-2.570.32941390.2616874X-RAY DIFFRACTION99.8
2.57-2.680.30031400.25886954X-RAY DIFFRACTION99.82
2.68-2.80.2991380.24296800X-RAY DIFFRACTION98.75
2.8-2.950.25811410.22986970X-RAY DIFFRACTION99.87
2.95-3.130.25881390.21796881X-RAY DIFFRACTION99.8
3.13-3.370.27791410.20956958X-RAY DIFFRACTION99.73
3.37-3.710.20971400.17696900X-RAY DIFFRACTION99.04
3.71-4.250.18191410.16036956X-RAY DIFFRACTION99.7
4.25-5.350.17211420.14777016X-RAY DIFFRACTION99.18
5.35-49.110.17091450.15597135X-RAY DIFFRACTION98.58
Refinement TLS params.Method: refined / Origin x: -12.4169408731 Å / Origin y: 28.8693663109 Å / Origin z: -70.918351869 Å
111213212223313233
T0.235973636211 Å20.00927065564165 Å2-0.00634192756435 Å2-0.188290566615 Å20.0299648967449 Å2--0.429599671282 Å2
L0.0979796163277 °20.0332205155202 °20.0021042620018 °2--0.0208460321999 °20.0197948855726 °2--0.0514704267993 °2
S-0.00331746831162 Å °0.00529461031345 Å °0.00911716105243 Å °-0.00244655548868 Å °0.0202872045499 Å °-0.0558461775113 Å °0.00032701013797 Å °0.00519800057883 Å °-0.0169626548316 Å °
Refinement TLS groupSelection details: all

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