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- PDB-4ixv: Crystal structure of human Arginase-2 complexed with inhibitor 2d... -

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Basic information

Entry
Database: PDB / ID: 4ixv
TitleCrystal structure of human Arginase-2 complexed with inhibitor 2d: {(5R)-5-amino-5-carboxy-5-[1-(4-chlorobenzyl)piperidin-4-yl]pentyl}(trihydroxy)borate(1-)
ComponentsArginase-2, mitochondrial
KeywordsHYDROLASE/HYDROLASE INHIBITOR / metalloenzyme / alpha/beta fold / Hydrolase / Arginine metabolism / Mitochondrion / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of chemokine (C-C motif) ligand 4 production / negative regulation of activated CD8-positive, alpha-beta T cell apoptotic process / negative regulation of macrophage inflammatory protein 1 alpha production / negative regulation of defense response to bacterium / negative regulation of type 2 immune response / negative regulation of interleukin-13 production / negative regulation of chemokine (C-C motif) ligand 5 production / regulation of interleukin-1 beta production / Urea cycle / arginase ...negative regulation of chemokine (C-C motif) ligand 4 production / negative regulation of activated CD8-positive, alpha-beta T cell apoptotic process / negative regulation of macrophage inflammatory protein 1 alpha production / negative regulation of defense response to bacterium / negative regulation of type 2 immune response / negative regulation of interleukin-13 production / negative regulation of chemokine (C-C motif) ligand 5 production / regulation of interleukin-1 beta production / Urea cycle / arginase / arginine catabolic process to ornithine / arginase activity / urea cycle / negative regulation of CD4-positive, alpha-beta T cell proliferation / negative regulation of interleukin-17 production / regulation of reactive oxygen species biosynthetic process / ureteric bud development / negative regulation of tumor necrosis factor production / striated muscle contraction / nitric oxide biosynthetic process / Mitochondrial protein degradation / positive regulation of cellular senescence / manganese ion binding / adaptive immune response / mitochondrial matrix / innate immune response / mitochondrion / cytoplasm
Similarity search - Function
Ureohydrolase domain / Arginase / Ureohydrolase, manganese-binding site / Arginase family signature. / Ureohydrolase / Arginase family / Arginase family profile. / Arginase; Chain A / Ureohydrolase domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
BENZAMIDINE / BETA-MERCAPTOETHANOL / : / Chem-XA1 / Arginase-2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsCousido-Siah, A. / Mitschler, A. / Ruiz, F.X. / Whitehouse, D. / Beckett, P. / Van Zandt, M.C. / Ji, M.K. / Ryder, T. / Jagdmann, R. / Andreoli, M. ...Cousido-Siah, A. / Mitschler, A. / Ruiz, F.X. / Whitehouse, D. / Beckett, P. / Van Zandt, M.C. / Ji, M.K. / Ryder, T. / Jagdmann, R. / Andreoli, M. / Olczak, J. / Mazur, M. / Czestkowski, W. / Piotrowska, W. / Schroeter, H. / Golebiowski, A. / Podjarny, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Synthesis of quaternary alpha-amino acid-based arginase inhibitors via the Ugi reaction.
Authors: Golebiowski, A. / Whitehouse, D. / Beckett, R.P. / Van Zandt, M. / Ji, M.K. / Ryder, T.R. / Jagdmann, E. / Andreoli, M. / Lee, Y. / Sheeler, R. / Conway, B. / Olczak, J. / Mazur, M. / ...Authors: Golebiowski, A. / Whitehouse, D. / Beckett, R.P. / Van Zandt, M. / Ji, M.K. / Ryder, T.R. / Jagdmann, E. / Andreoli, M. / Lee, Y. / Sheeler, R. / Conway, B. / Olczak, J. / Mazur, M. / Czestkowski, W. / Piotrowska, W. / Cousido-Siah, A. / Ruiz, F.X. / Mitschler, A. / Podjarny, A. / Schroeter, H.
History
DepositionJan 28, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2017Group: Refinement description / Category: software
Revision 1.2Sep 20, 2023Group: 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 / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _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_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_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 / _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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Arginase-2, mitochondrial
B: Arginase-2, mitochondrial
C: Arginase-2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,81918
Polymers99,6953
Non-polymers2,12415
Water11,403633
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Arginase-2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9406
Polymers33,2321
Non-polymers7085
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: Arginase-2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9406
Polymers33,2321
Non-polymers7085
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
C: Arginase-2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9406
Polymers33,2321
Non-polymers7085
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)128.123, 128.123, 159.362
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number94
Space group name H-MP42212
Components on special symmetry positions
IDModelComponents
11B-592-

HOH

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Components

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Protein , 1 types, 3 molecules ABC

#1: Protein Arginase-2, mitochondrial / Kidney-type arginase / Non-hepatic arginase / Type II arginase


Mass: 33231.656 Da / Num. of mol.: 3 / Fragment: UNP residues 24-329
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARG2 / Plasmid: pET23b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P78540, arginase

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Non-polymers , 5 types, 648 molecules

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


Mass: 54.938 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mn
#3: Chemical ChemComp-BEN / BENZAMIDINE


Mass: 120.152 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C7H8N2
#4: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS
#5: Chemical ChemComp-XA1 / {(5R)-5-amino-5-carboxy-5-[1-(4-chlorobenzyl)piperidin-4-yl]pentyl}(trihydroxy)borate(1-)


Mass: 399.697 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C18H29BClN2O5
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 633 / Source method: isolated from a natural source / Formula: H2O

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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: 3.28 Å3/Da / Density % sol: 62.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: Crystals in condition H3 from Silver Bullet screen (Hampton Research) using Tacsimate in the reservoir, pH 7, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Oct 6, 2009 / Details: OSMIC MIRRORS
RadiationMonochromator: DOUBLE MIRRORS MONOCHROMATOR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.3→33.83 Å / Num. all: 54972 / Num. obs: 54972 / % possible obs: 92.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.4 % / Rsym value: 0.128 / Net I/σ(I): 11.3
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 4.4 % / Mean I/σ(I) obs: 3.6 / Rsym value: 0.355 / % possible all: 97.6

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIX1.8_1069refinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1D3V

1d3v


Resolution: 2.3→33.83 Å / Occupancy max: 1 / Occupancy min: 0.1 / FOM work R set: 0.8473 / SU ML: 0.25 / Cross valid method: R-free / σ(F): 0 / σ(I): 0 / Phase error: 21.88 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2318 2774 5.05 %Random 5%
Rwork0.1802 ---
all0.1828 54957 --
obs0.1828 54957 92.38 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 100.43 Å2 / Biso mean: 17.6987 Å2 / Biso min: 1.54 Å2
Refinement stepCycle: LAST / Resolution: 2.3→33.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7010 0 126 633 7769
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.017446
X-RAY DIFFRACTIONf_angle_d1.4310174
X-RAY DIFFRACTIONf_chiral_restr0.1771165
X-RAY DIFFRACTIONf_plane_restr0.0071334
X-RAY DIFFRACTIONf_dihedral_angle_d13.8152777
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3-2.3390.25561330.18652608274194
2.339-2.38150.23271420.17952724286698
2.3815-2.42730.27161450.17812712285798
2.4273-2.47680.25221420.17892714285698
2.4768-2.53070.22431440.17642720286498
2.5307-2.58950.27671600.17252702286298
2.5895-2.65430.23731550.17682713286897
2.6543-2.7260.24771480.1842721286997
2.726-2.80620.24231500.18012715286597
2.8062-2.89670.27431350.18572715285097
2.8967-3.00020.23851360.19232741287797
3.0002-3.12020.24341330.18922770290398
3.1202-3.26210.25351510.18822738288998
3.2621-3.4340.22711440.18242712285697
3.434-3.64890.2381390.16582685282494
3.6489-3.93020.21531550.16582483263888
3.9302-4.3250.18781110.17092363247483
4.325-4.94920.19421160.16652123223974
4.9492-6.22910.19861390.18582459259885
6.2291-33.83520.2671960.21152065216167

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