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- PDB-4ixu: Crystal structure of human Arginase-2 complexed with inhibitor 11... -

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Basic information

Entry
Database: PDB / ID: 4ixu
TitleCrystal structure of human Arginase-2 complexed with inhibitor 11d: {(5R)-5-amino-5-carboxy-5-[(3-endo)-8-(3,4-dichlorobenzyl)-8-azabicyclo[3.2.1]oct-3-yl]pentyl}(trihydroxy)borate(1-)
ComponentsArginase-2, mitochondrial
KeywordsHYDROLASE/HYDROLASE INHIBITOR / metalloenzyme / alpha/beta fold / Hydrolase / Arginine metabolism / Manganese / boronate / 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 defense response to bacterium / negative regulation of macrophage inflammatory protein 1 alpha production / 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 defense response to bacterium / negative regulation of macrophage inflammatory protein 1 alpha production / 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 / : / arginase activity / urea cycle / negative regulation of CD4-positive, alpha-beta T cell proliferation / negative regulation of interleukin-17 production / ureteric bud development / regulation of reactive oxygen species biosynthetic process / 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
Arginase / Ureohydrolase domain / 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
Chem-38I / BENZAMIDINE / BETA-MERCAPTOETHANOL / : / Arginase-2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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 1.1Sep 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)102,23421
Polymers99,6953
Non-polymers2,53918
Water14,376798
1
A: Arginase-2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0787
Polymers33,2321
Non-polymers8466
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Arginase-2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0787
Polymers33,2321
Non-polymers8466
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Arginase-2, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0787
Polymers33,2321
Non-polymers8466
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)127.400, 127.400, 159.249
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
11A-568-

HOH

21A-613-

HOH

31C-716-

HOH

Detailsbiological assembly is a homotrimer with one copy in the asymmetric unit

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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
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, 816 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.: 6 / Source method: obtained synthetically / Formula: C2H6OS
#5: Chemical ChemComp-38I / {(5R)-5-amino-5-carboxy-5-[(3-endo)-8-(3,4-dichlorobenzyl)-8-azabicyclo[3.2.1]oct-3-yl]pentyl}(trihydroxy)borate(1-)


Mass: 460.180 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C20H30BCl2N2O5
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 798 / 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: 3.24 Å3/Da / Density % sol: 62.05 %
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: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.9191 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jul 8, 2011
RadiationMonochromator: BARTELS MONOCHROMATOR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9191 Å / Relative weight: 1
ReflectionResolution: 1.9→46.34 Å / Num. all: 103422 / Num. obs: 103343 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.4 % / Biso Wilson estimate: 24.11 Å2 / Rsym value: 0.082 / Net I/σ(I): 19.3
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 6.4 % / Mean I/σ(I) obs: 3.6 / Rsym value: 0.516 / % possible all: 100

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Processing

Software
NameVersionClassificationNB
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: 1.9→46.335 Å / Occupancy max: 1 / Occupancy min: 0 / FOM work R set: 0.8844 / SU ML: 0.15 / Cross valid method: R-free / σ(F): 0 / σ(I): 0 / Phase error: 18.3 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1932 5167 5 %Random 5%
Rwork0.1673 ---
all0.1686 103326 --
obs0.1686 103326 99.92 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 127.09 Å2 / Biso mean: 19.1735 Å2 / Biso min: 4.53 Å2
Refinement stepCycle: LAST / Resolution: 1.9→46.335 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7010 0 147 798 7955
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0097491
X-RAY DIFFRACTIONf_angle_d1.48510245
X-RAY DIFFRACTIONf_chiral_restr0.1261177
X-RAY DIFFRACTIONf_plane_restr0.0071340
X-RAY DIFFRACTIONf_dihedral_angle_d14.0782803
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.9-1.92070.28121770.21293175335299
1.9207-1.94330.24881900.203832043394100
1.9433-1.9670.23041660.202632513417100
1.967-1.99190.23841590.195732263385100
1.9919-2.01810.21731660.192532573423100
2.0181-2.04570.23331780.192431993377100
2.0457-2.07490.23811620.179432413403100
2.0749-2.10590.20731680.172632513419100
2.1059-2.13880.18981700.170432223392100
2.1388-2.17390.21561600.173532483408100
2.1739-2.21140.18391550.172732683423100
2.2114-2.25160.19811880.169832283416100
2.2516-2.29490.21651610.162332413402100
2.2949-2.34170.18761470.166733013448100
2.3417-2.39260.20821900.1631973387100
2.3926-2.44830.19141690.164132793448100
2.4483-2.50950.19191730.157332483421100
2.5095-2.57740.2081710.165832533424100
2.5774-2.65320.19591800.171332793459100
2.6532-2.73880.21961620.174332663428100
2.7388-2.83670.22161700.176432913461100
2.8367-2.95030.21021710.174932663437100
2.9503-3.08450.19841610.179532893450100
3.0845-3.24710.20941790.171132793458100
3.2471-3.45050.18081920.164833003492100
3.4505-3.71680.18271760.153532963472100
3.7168-4.09060.16821750.1533353510100
4.0906-4.68210.15611590.135233523511100
4.6821-5.8970.16132110.167833703581100
5.897-46.34860.19051810.17833547372899

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