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- PDB-6v7d: Human Arginase1 Complexed with Bicyclic Inhibitor Compound 10 -

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Basic information

Entry
Database: PDB / ID: 6v7d
TitleHuman Arginase1 Complexed with Bicyclic Inhibitor Compound 10
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 / arginine catabolic process to ornithine / arginase / 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 / arginine catabolic process to ornithine / arginase / 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-QR4 / Arginase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsPalte, R.L. / Lesburg, C.A.
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)210,98924
Polymers208,6796
Non-polymers2,31018
Water15,439857
1
A: Arginase-1
B: Arginase-1
E: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,49512
Polymers104,3403
Non-polymers1,1559
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5720 Å2
ΔGint-16 kcal/mol
Surface area33590 Å2
MethodPISA
2
C: Arginase-1
D: Arginase-1
F: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,49512
Polymers104,3403
Non-polymers1,1559
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5680 Å2
ΔGint-17 kcal/mol
Surface area33400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.660, 285.720, 67.230
Angle α, β, γ (deg.)90.000, 90.100, 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-QR4 / {3-[(3aR,4R,5S,6aR)-4-azaniumyl-4-carboxyoctahydrocyclopenta[b]pyrrol-1-ium-5-yl]propyl}(trihydroxy)borate(1-)


Mass: 275.130 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: C11H24BN2O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 857 / 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: 2.47 Å3/Da / Density % sol: 50.2 %
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: Dec 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.82→71.43 Å / Num. obs: 162702 / % possible obs: 90.1 % / Redundancy: 3.1 % / CC1/2: 0.99 / Rmerge(I) obs: 0.12 / Net I/σ(I): 6.8
Reflection shellResolution: 1.82→1.85 Å / Rmerge(I) obs: 0.48 / Num. unique obs: 8486 / CC1/2: 0.78

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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: 1.82→26.65 Å / Cor.coef. Fo:Fc: 0.805 / Cor.coef. Fo:Fc free: 0.777 / SU R Cruickshank DPI: 0.16 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.157 / SU Rfree Blow DPI: 0.135 / SU Rfree Cruickshank DPI: 0.138
RfactorNum. reflection% reflectionSelection details
Rfree0.236 7998 4.94 %RANDOM
Rwork0.215 ---
obs0.216 161956 90 %-
Displacement parametersBiso max: 125.17 Å2 / Biso mean: 17.84 Å2 / Biso min: 3.01 Å2
Baniso -1Baniso -2Baniso -3
1-6.1937 Å20 Å20.6704 Å2
2---14.6709 Å20 Å2
3---8.4772 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 1.82→26.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14511 0 264 857 15632
Biso mean--14.65 17.45 -
Num. residues----1911
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d5232SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes312HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2177HARMONIC5
X-RAY DIFFRACTIONt_it15121HARMONIC20
X-RAY DIFFRACTIONt_nbd6SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1984SEMIHARMONIC5
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_contact18766SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d15121HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg20671HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.21
X-RAY DIFFRACTIONt_other_torsion15.51
LS refinement shellResolution: 1.82→1.87 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2636 618 4.91 %
Rwork0.2267 11968 -
all0.2285 12586 -
obs--94.36 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.11980.1171-0.09630.1040.1510.2814-0.01550.06610.01110.01840.0176-0.06280.008-0.011-0.0022-0.01530.00130.0237-0.0517-0.0152-0.068713.2261-1.268910.5506
20.24630.1006-0.27430.14920.00930.4968-0.0133-0.0081-0.01550.0114-0.0054-0.00960.0122-0.04040.0187-0.030.00080.0139-0.0331-0.0167-0.0753-11.0359-5.243643.1099
30.24610.01020.13430.19240.09110.33080.0031-0.0629-0.0155-0.03340.0165-0.0445-0.0139-0.0002-0.0196-0.02530.00290.0106-0.0555-0.0172-0.0621-13.580542.362920.6325
40.3228-0.18390.21020.1649-0.08920.42070.01450.03510.0071-0.0048-0.0108-0.0020.00820.0069-0.0037-0.0351-0.00160.0038-0.0427-0.0185-0.0647-37.805746.5243-12.0114
50.38410.0396-0.22190.3120.08510.4629-0.00190.0187-0.04520.01540.006-0.04080.1027-0.0604-0.00420.0137-0.0430.0262-0.0935-0.0339-0.0886-7.5302-35.968116.4637
60.3749-0.0741-0.00360.40250.16910.4149-0.00620.00150.05160.00730.0243-0.0445-0.0894-0.0184-0.01810.00460.0310.0136-0.0986-0.0191-0.0857-34.410277.097914.7218
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A2 - 319
2X-RAY DIFFRACTION2{ B|* }B2 - 320
3X-RAY DIFFRACTION3{ C|* }C2 - 319
4X-RAY DIFFRACTION4{ D|* }D2 - 319
5X-RAY DIFFRACTION5{ E|* }E2 - 320
6X-RAY DIFFRACTION6{ F|* }F2 - 320

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