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- PDB-6v7e: Human Arginase1 Complexed with Bicyclic Inhibitor Compound 12 -

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Basic information

Entry
Database: PDB / ID: 6v7e
TitleHuman Arginase1 Complexed with Bicyclic Inhibitor Compound 12
ComponentsArginase-1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / AGONIST / ARG (ARGINASE) / BICYCLIC / IMMUNOTHERAPY / METALLOENZYME / HYDROLASE / HYDROLASE-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 / arginine catabolic process to ornithine / arginase activity / 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 / arginine catabolic process to ornithine / arginase activity / 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 / cytosol / 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
: / Chem-QRA / Arginase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsPalte, R.L.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.
Authors: Mitcheltree, M.J. / Li, D. / Achab, A. / Beard, A. / Chakravarthy, K. / Cheng, M. / Cho, H. / Eangoor, P. / Fan, P. / Gathiaka, S. / Kim, H.Y. / Lesburg, C.A. / Lyons, T.W. / Martinot, T.A. ...Authors: Mitcheltree, M.J. / Li, D. / Achab, A. / Beard, A. / Chakravarthy, K. / Cheng, M. / Cho, H. / Eangoor, P. / Fan, P. / Gathiaka, S. / Kim, H.Y. / Lesburg, C.A. / Lyons, T.W. / Martinot, T.A. / Miller, J.R. / McMinn, S. / O'Neil, J. / Palani, A. / Palte, R.L. / Sauri, J. / Sloman, D.L. / Zhang, H. / Cumming, J.N. / Fischer, C.
History
DepositionDec 8, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 6, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 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 / software / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name / _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

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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)211,06124
Polymers208,6796
Non-polymers2,38218
Water20,0151111
1
A: Arginase-1
B: Arginase-1
E: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,53112
Polymers104,3403
Non-polymers1,1919
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5680 Å2
ΔGint-14 kcal/mol
Surface area33780 Å2
MethodPISA
2
C: Arginase-1
D: Arginase-1
F: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,53112
Polymers104,3403
Non-polymers1,1919
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5670 Å2
ΔGint-15 kcal/mol
Surface area33810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.720, 286.490, 67.120
Angle α, β, γ (deg.)90.000, 90.030, 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 / Plasmid: pET24 / 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-QRA / 3-[(5~{S},7~{S},8~{S})-8-azanyl-8-carboxy-1-azaspiro[4.4]nonan-7-yl]propyl-$l^{3}-oxidanyl-bis(oxidanyl)boranuide


Mass: 287.140 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C12H24BN2O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1111 / 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: 50.3 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7
Details: 10% MMT (pH 7.0) 0.1 M 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: Feb 7, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.99→71.62 Å / Num. obs: 136926 / % possible obs: 98.5 % / Redundancy: 3.4 % / CC1/2: 0.99 / Rmerge(I) obs: 0.11 / Net I/σ(I): 8.6
Reflection shellResolution: 1.99→2.02 Å / Rmerge(I) obs: 0.64 / Num. unique obs: 6825 / CC1/2: 0.75

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
autoPROCdata scaling
autoBUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6V7C

6v7c


Resolution: 1.99→71.62 Å / Cor.coef. Fo:Fc: 0.883 / Cor.coef. Fo:Fc free: 0.851 / SU R Cruickshank DPI: 0.198 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.198 / SU Rfree Blow DPI: 0.167 / SU Rfree Cruickshank DPI: 0.169
RfactorNum. reflection% reflectionSelection details
Rfree0.249 6694 4.93 %RANDOM
Rwork0.214 ---
obs0.216 135880 98.5 %-
Displacement parametersBiso max: 153.76 Å2 / Biso mean: 25.74 Å2 / Biso min: 7.31 Å2
Baniso -1Baniso -2Baniso -3
1--3.1232 Å20 Å2-2.3913 Å2
2---7.2721 Å20 Å2
3---10.3954 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: final / Resolution: 1.99→71.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14454 0 132 1111 15697
Biso mean--22.62 29.22 -
Num. residues----1902
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d5172SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes312HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2148HARMONIC5
X-RAY DIFFRACTIONt_it14880HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1956SEMIHARMONIC5
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_contact18723SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d14880HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg20214HARMONIC30.91
X-RAY DIFFRACTIONt_omega_torsion3.44
X-RAY DIFFRACTIONt_other_torsion16.79
LS refinement shellResolution: 1.99→2.04 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2543 463 4.57 %
Rwork0.2248 9679 -
all0.2262 10142 -
obs--99.67 %

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