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- PDB-8rfa: Arginase 2 in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 8rfa
TitleArginase 2 in complex with an inhibitor
ComponentsArginase-2, mitochondrial
KeywordsHYDROLASE / Arginase / 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 / 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
Arginase / Ureohydrolase, manganese-binding site / Arginase family signature. / Ureohydrolase / Arginase family / Arginase family profile. / Ureohydrolase domain superfamily
Similarity search - Domain/homology
: / : / Arginase-2, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.76 Å
AuthorsPetersen, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: J.Med.Chem. / Year: 2024
Title: Discovery of (2 R ,4 R )-4-(( S )-2-Amino-3-methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic Acid (AZD0011), an Actively Transported Prodrug of a Potent Arginase Inhibitor to Treat Cancer.
Authors: Mlynarski, S.N. / Aquila, B.M. / Cantin, S. / Cook, S. / Doshi, A. / Finlay, M.R.V. / Gangl, E.T. / Grebe, T. / Gu, C. / Kawatkar, S.P. / Petersen, J. / Pop-Damkov, P. / Schuller, A.G. / ...Authors: Mlynarski, S.N. / Aquila, B.M. / Cantin, S. / Cook, S. / Doshi, A. / Finlay, M.R.V. / Gangl, E.T. / Grebe, T. / Gu, C. / Kawatkar, S.P. / Petersen, J. / Pop-Damkov, P. / Schuller, A.G. / Shao, W. / Shields, J.D. / Simpson, I. / Tavakoli, S. / Tentarelli, S. / Throner, S. / Wang, H. / Wang, J. / Wu, D. / Ye, Q.
#1: Journal: J.Med.Chem. / Year: 2024
Title: Design and Synthesis of Acyclic Boronic Acid Arginase Inhibitors.
Authors: Shields, J.D. / Aquila, B.M. / Emmons, D. / Finlay, M.R.V. / Gangl, E.T. / Gu, C. / Mlynarski, S.N. / Petersen, J. / Pop-Damkov, P. / Sha, L. / Simpson, I. / Tavakoli, S. / Tentarelli, S. / ...Authors: Shields, J.D. / Aquila, B.M. / Emmons, D. / Finlay, M.R.V. / Gangl, E.T. / Gu, C. / Mlynarski, S.N. / Petersen, J. / Pop-Damkov, P. / Sha, L. / Simpson, I. / Tavakoli, S. / Tentarelli, S. / Wang, H. / Ye, Q. / Zheng, X.
History
DepositionDec 12, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
Revision 2.0Dec 4, 2024Group: Database references / Non-polymer description / Category: chem_comp / citation / citation_author / Item: _chem_comp.formula
Revision 2.1Dec 25, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)110,51110
Polymers109,9603
Non-polymers5517
Water7,278404
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7140 Å2
ΔGint-53 kcal/mol
Surface area34900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.660, 134.870, 144.300
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 36653.367 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARG2 / Production host: Escherichia coli (E. coli) / References: UniProt: P78540, arginase
#2: Chemical
ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mn
#3: Chemical ChemComp-A1HZ9 / [(4~{R},5~{S})-4-(aminomethyl)-5-azanyl-6-oxidanyl-6-oxidanylidene-hexyl]-tris(oxidanyl)boron


Mass: 221.039 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H18BN2O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 404 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.06 Å3/Da / Density % sol: 40.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 13-18% PEG3350 and 0.2-0.35M Ammonium Citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jul 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.755→44.4 Å / Num. obs: 91988 / % possible obs: 99.9 % / Redundancy: 6.3 % / Rmerge(I) obs: 0.053 / Rpim(I) all: 0.023 / Rrim(I) all: 0.058 / Net I/σ(I): 16.3
Reflection shellResolution: 1.755→1.785 Å / % possible obs: 99.9 % / Redundancy: 6 % / Rmerge(I) obs: 0.757 / Num. measured all: 27678 / Num. unique obs: 4583 / Rpim(I) all: 0.334 / Rrim(I) all: 0.829 / Net I/σ(I) obs: 2.1

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Processing

Software
NameVersionClassification
BUSTER2.11.7 PACIOREKrefinement
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.76→44.4 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.912 / SU R Cruickshank DPI: 0.137 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.139 / SU Rfree Blow DPI: 0.128 / SU Rfree Cruickshank DPI: 0.127
RfactorNum. reflection% reflectionSelection details
Rfree0.252 4377 4.8 %RANDOM
Rwork0.222 ---
obs0.223 91199 99.9 %-
Displacement parametersBiso mean: 44.16 Å2
Baniso -1Baniso -2Baniso -3
1--12.5646 Å20 Å20 Å2
2--2.0356 Å20 Å2
3---10.5291 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: LAST / Resolution: 1.76→44.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7123 0 21 404 7548
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.017290HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.069916HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2455SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes172HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1066HARMONIC5
X-RAY DIFFRACTIONt_it7290HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.35
X-RAY DIFFRACTIONt_other_torsion17.54
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion964SEMIHARMONIC5
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_contact8854SEMIHARMONIC4
LS refinement shellResolution: 1.76→1.81 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3056 316 4.73 %
Rwork0.2656 6365 -
all0.2674 6681 -
obs--99.96 %

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