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- PDB-8e5m: Structure of ARG1 complex with pyrrolidine-based non-boronic acid... -

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Basic information

Entry
Database: PDB / ID: 8e5m
TitleStructure of ARG1 complex with pyrrolidine-based non-boronic acid inhibitor 6
ComponentsArginase-1
KeywordsHYDROLASE/INHIBITOR / Arginase / hydrolase / urea cycle / metabolism / HYDROLASE-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
: / Chem-UKR / Arginase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.84 Å
AuthorsPalte, R.L. / Gathiaka, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2023
Title: Discovery of non-boronic acid Arginase 1 inhibitors through virtual screening and biophysical methods.
Authors: Gathiaka, S. / Palte, R.L. / So, S.S. / Chai, X. / Richard Miller, J. / Kuvelkar, R. / Wen, X. / Cifelli, S. / Kreamer, A. / Liaw, A. / McLaren, D.G. / Fischer, C.
History
DepositionAug 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.title / _citation_author.name
Revision 1.2Oct 25, 2023Group: 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)212,78724
Polymers208,6796
Non-polymers4,10818
Water20,2851126
1
A: Arginase-1
B: Arginase-1
E: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,39312
Polymers104,3403
Non-polymers2,0549
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6420 Å2
ΔGint-49 kcal/mol
Surface area33740 Å2
MethodPISA
2
C: Arginase-1
D: Arginase-1
F: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,39312
Polymers104,3403
Non-polymers2,0549
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6400 Å2
ΔGint-52 kcal/mol
Surface area33880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.470, 286.100, 67.350
Angle α, β, γ (deg.)90.000, 90.320, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#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
Source: (gene. exp.) Homo sapiens (human) / Gene: ARG1 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P05089, arginase
#2: Chemical
ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Mn
#3: Chemical
ChemComp-UKR / 1-{[(3S,4S)-3-({4-[2-(4-fluorobenzene-1-sulfonyl)ethyl]piperidin-1-yl}methyl)-4-(3-fluorophenyl)pyrrolidin-1-yl]methyl}cyclopentane-1-carboxylic acid


Mass: 574.722 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C31H40F2N2O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1126 / Source method: isolated from a natural source / Formula: H2O
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: 2.48 Å3/Da / Density % sol: 50.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 10% MMT (pH 7.0), 0.1 ammonium formate, 16-22% PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 5, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.84→71.88 Å / Num. obs: 158294 / % possible obs: 91.4 % / Redundancy: 3.4 % / CC1/2: 0.997 / Net I/σ(I): 10.9
Reflection shellResolution: 1.84→1.875 Å / Num. unique obs: 28817 / CC1/2: 0.739

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
autoBUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6V7C

6v7c


Resolution: 1.84→71.52 Å / Cor.coef. Fo:Fc: 0.92 / Cor.coef. Fo:Fc free: 0.898 / SU R Cruickshank DPI: 0.154 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.154 / SU Rfree Blow DPI: 0.138 / SU Rfree Cruickshank DPI: 0.139
RfactorNum. reflection% reflectionSelection details
Rfree0.231 7845 4.96 %RANDOM
Rwork0.198 ---
obs0.199 158289 91 %-
Displacement parametersBiso max: 124.11 Å2 / Biso mean: 29 Å2 / Biso min: 9.52 Å2
Baniso -1Baniso -2Baniso -3
1--1.479 Å20 Å24.1036 Å2
2---4.9895 Å20 Å2
3---6.4686 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: final / Resolution: 1.84→71.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14454 0 252 1126 15832
Biso mean--34.66 33.18 -
Num. residues----1902
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d5238SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes312HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2244HARMONIC5
X-RAY DIFFRACTIONt_it15018HARMONIC20
X-RAY DIFFRACTIONt_nbd4SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1968SEMIHARMONIC5
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_contact19131SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d15018HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg20400HARMONIC21.12
X-RAY DIFFRACTIONt_omega_torsion3.38
X-RAY DIFFRACTIONt_other_torsion17.07
LS refinement shellResolution: 1.84→1.89 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2392 579 5.02 %
Rwork0.2091 10966 -
all0.2106 11545 -
obs--90.22 %

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