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- PDB-6ss2: Structure of arginase-2 in complex with the inhibitory human anti... -

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Basic information

Entry
Database: PDB / ID: 6ss2
TitleStructure of arginase-2 in complex with the inhibitory human antigen-binding fragment Fab C0021158
Components
  • (Fab C0021158 ...) x 2
  • Arginase-2, mitochondrial
KeywordsPROTEIN BINDING / arginase-2 inhibitor / IgG / antigen-binding fragment
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 chemokine (C-C motif) ligand 5 production / negative regulation of interleukin-13 production / regulation of interleukin-1 beta production / Urea cycle / arginine catabolic process to ornithine ...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 chemokine (C-C motif) ligand 5 production / negative regulation of interleukin-13 production / regulation of interleukin-1 beta production / Urea cycle / arginine catabolic process to ornithine / 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 / 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: 2.4 Å
AuthorsBurschowsky, D. / Addyman, A. / Fiedler, S. / Groves, M. / Haynes, S. / Seewooruthun, C. / Carr, M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKC1362/A20263 United Kingdom
CitationJournal: Mabs
Title: Structural and functional characterization of C0021158, a high-affinity monoclonal antibody that inhibits Arginase 2 function via a novel non-competitive mechanism of action.
Authors: Austin, M. / Burschowsky, D. / Chan, D.T.Y. / Jenkinson, L. / Haynes, S. / Diamandakis, A. / Seewooruthun, C. / Addyman, A. / Fiedler, S. / Ryman, S. / Whitehouse, J. / Slater, L.H. / ...Authors: Austin, M. / Burschowsky, D. / Chan, D.T.Y. / Jenkinson, L. / Haynes, S. / Diamandakis, A. / Seewooruthun, C. / Addyman, A. / Fiedler, S. / Ryman, S. / Whitehouse, J. / Slater, L.H. / Hadjinicolaou, A.V. / Gileadi, U. / Gowans, E. / Shibata, Y. / Barnard, M. / Kaserer, T. / Sharma, P. / Luheshi, N.M. / Wilkinson, R.W. / Vaughan, T.J. / Holt, S.V. / Cerundolo, V. / Carr, M.D. / Groves, M.A.T.
History
DepositionSep 6, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 10, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 16, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / struct_conn / struct_conn_type
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_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_conn.ptnr2_label_seq_id / _struct_conn_type.id
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Arginase-2, mitochondrial
HHH: Fab C0021158 heavy chain (IgG1)
LLL: Fab C0021158 light chain (IgG1)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,47142
Polymers84,8863
Non-polymers3,58539
Water1,06359
1
AAA: Arginase-2, mitochondrial
HHH: Fab C0021158 heavy chain (IgG1)
LLL: Fab C0021158 light chain (IgG1)
hetero molecules

AAA: Arginase-2, mitochondrial
HHH: Fab C0021158 heavy chain (IgG1)
LLL: Fab C0021158 light chain (IgG1)
hetero molecules

AAA: Arginase-2, mitochondrial
HHH: Fab C0021158 heavy chain (IgG1)
LLL: Fab C0021158 light chain (IgG1)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)265,413126
Polymers254,6599
Non-polymers10,754117
Water1629
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Buried area43650 Å2
ΔGint-766 kcal/mol
Surface area93610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)149.061, 149.061, 123.287
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3

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Components

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Protein , 1 types, 1 molecules AAA

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


Mass: 37100.859 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARG2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P78540, arginase

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Antibody , 2 types, 2 molecules HHHLLL

#2: Antibody Fab C0021158 heavy chain (IgG1)


Mass: 24647.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Amino acids are numbered according to the Kabat numbering scheme.
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pEU1.3 fab / Cell line (production host): CHO / Production host: Cricetulus griseus (Chinese hamster) / Variant (production host): ExpiCHO
#3: Antibody Fab C0021158 light chain (IgG1)


Mass: 23137.520 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Amino acids are numbered according to the Kabat numbering scheme. Residue 10 would not be present in the Kabat scheme, but due to problems with non-continuous numbering in L-peptides, we ...Details: Amino acids are numbered according to the Kabat numbering scheme. Residue 10 would not be present in the Kabat scheme, but due to problems with non-continuous numbering in L-peptides, we included it. Therefore, residues 2-10 should be read as 1-9, per Kabat.
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pEU1.3 fab / Cell line (production host): CHO / Production host: Cricetulus griseus (Chinese hamster) / Variant (production host): ExpiCHO

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Non-polymers , 4 types, 98 molecules

#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#6: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 59 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 3.11 Å3/Da / Density % sol: 60.39 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: Crystallisation condition: 2 M (NH4)2SO4 Seed condition (approx. final conc.) 20 mM MIB (malonate, imidazole, boric acid) 4% glycerol 2% PEG4000 9 mM NaNO3 9 mM Na2HPO4 9 mM (NH4)2SO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jan 17, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
Reflection twin
TypeCrystal-IDIDOperatorDomain-IDFraction
pseudo-merohedral11H, K, L10.8011
pseudo-merohedral22K, H, -L20.1989
ReflectionResolution: 2.4→45.37 Å / Num. obs: 39908 / % possible obs: 99.9 % / Redundancy: 5.2 % / CC1/2: 0.99 / Rmerge(I) obs: 0.17 / Net I/σ(I): 7
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 5.4 % / Rmerge(I) obs: 1.72 / Mean I/σ(I) obs: 1 / Num. unique obs: 4198 / CC1/2: 0.36 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0253refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6SS4, 6SRX

6ss4

6srx


Resolution: 2.4→45.368 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.93 / SU B: 10.443 / SU ML: 0.128 / Cross valid method: FREE R-VALUE / ESU R: 0.085 / ESU R Free: 0.058
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2842 1976 4.952 %
Rwork0.2538 --
all0.255 --
obs-39901 99.88 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 48.54 Å2
Baniso -1Baniso -2Baniso -3
1-1.969 Å20 Å20 Å2
2--1.969 Å20 Å2
3----3.938 Å2
Refinement stepCycle: LAST / Resolution: 2.4→45.368 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5680 0 207 59 5946
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0135993
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175436
X-RAY DIFFRACTIONr_angle_refined_deg1.4131.6388128
X-RAY DIFFRACTIONr_angle_other_deg1.1371.5712664
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5365752
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.50922.55251
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.5515915
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.1361528
X-RAY DIFFRACTIONr_chiral_restr0.0540.2774
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026525
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021153
X-RAY DIFFRACTIONr_nbd_refined0.1890.2980
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1720.24965
X-RAY DIFFRACTIONr_nbtor_refined0.1560.22718
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0730.22835
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1660.2164
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0380.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1990.225
X-RAY DIFFRACTIONr_nbd_other0.2120.260
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.180.27
X-RAY DIFFRACTIONr_mcbond_it1.0263.2383017
X-RAY DIFFRACTIONr_mcbond_other1.0233.2383016
X-RAY DIFFRACTIONr_mcangle_it1.7044.8543766
X-RAY DIFFRACTIONr_mcangle_other1.7044.8553767
X-RAY DIFFRACTIONr_scbond_it1.3933.4772975
X-RAY DIFFRACTIONr_scbond_other1.1223.372906
X-RAY DIFFRACTIONr_scangle_it1.5935.1274361
X-RAY DIFFRACTIONr_scangle_other1.4184.9694260
X-RAY DIFFRACTIONr_lrange_it4.40537.65996
X-RAY DIFFRACTIONr_lrange_other4.33837.5645986
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.4620.7691600.8472818X-RAY DIFFRACTION100
2.462-2.530.7831300.7692737X-RAY DIFFRACTION99.9303
2.53-2.6030.721390.7112643X-RAY DIFFRACTION99.8923
2.603-2.6830.8761300.6212573X-RAY DIFFRACTION99.9261
2.683-2.770.5551150.4942525X-RAY DIFFRACTION99.6226
2.77-2.8670.4091450.3992381X-RAY DIFFRACTION99.9209
2.867-2.9750.3751400.3342348X-RAY DIFFRACTION100
2.975-3.0960.3171290.2822200X-RAY DIFFRACTION99.8285
3.096-3.2330.3121130.2412151X-RAY DIFFRACTION99.8677
3.233-3.390.241860.1912089X-RAY DIFFRACTION99.9081
3.39-3.5720.2131110.1831932X-RAY DIFFRACTION100
3.572-3.7870.197880.1721870X-RAY DIFFRACTION99.847
3.787-4.0470.166740.1541754X-RAY DIFFRACTION100
4.047-4.3680.1751000.1411603X-RAY DIFFRACTION99.9413
4.368-4.780.165730.1351501X-RAY DIFFRACTION99.7465
4.78-5.3370.131690.1381349X-RAY DIFFRACTION99.5088
5.337-6.1490.174470.161194X-RAY DIFFRACTION99.8391
6.149-7.4960.202500.1631026X-RAY DIFFRACTION100
7.496-10.460.194580.176768X-RAY DIFFRACTION99.7585
10.46-45.3680.31190.232463X-RAY DIFFRACTION99.793
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)
10.84450.14940.31891.41060.17521.6565-0.0104-0.1096-0.13440.11850.04160.08950.1376-0.0934-0.03110.02190.00170.01180.01990.03360.1948-10.4685-21.269910.8871
20.39190.180.81150.23330.11573.1571-0.11940.27770.0142-0.20630.1414-0.0902-0.15430.2397-0.02210.26-0.02340.02060.30580.00510.3648-19.8956-19.3957-43.1582
30.42990.3760.82720.68330.46361.9416-0.14190.01480.0757-0.14480.0517-0.0131-0.3137-0.10660.09020.11170.0116-0.02550.12930.00270.3227-34.4796-12.6966-38.6427
Refinement TLS group
IDRefine-IDRefine TLS-IDSelectionAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1ALLAAA22 - 341
2X-RAY DIFFRACTION2ALLHHH1 - 215
3X-RAY DIFFRACTION3ALLLLL2 - 210

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