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- PDB-6v7f: Human Arginase1 Complexed with Bicyclic Inhibitor Compound 13 -

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Basic information

Entry
Database: PDB / ID: 6v7f
TitleHuman Arginase1 Complexed with Bicyclic Inhibitor Compound 13
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-QRJ / Arginase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.02 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)211,07324
Polymers208,6796
Non-polymers2,39418
Water14,520806
1
A: Arginase-1
B: Arginase-1
E: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,53712
Polymers104,3403
Non-polymers1,1979
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5770 Å2
ΔGint-16 kcal/mol
Surface area33420 Å2
MethodPISA
2
C: Arginase-1
D: Arginase-1
F: Arginase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,53712
Polymers104,3403
Non-polymers1,1979
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5700 Å2
ΔGint-14 kcal/mol
Surface area33400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.510, 285.560, 67.160
Angle α, β, γ (deg.)90.000, 90.040, 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 / Cell (production host): BL21 / 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-QRJ / {3-[(5R,7S,8S)-8-azaniumyl-8-carboxy-2-azaspiro[4.4]nonan-2-ium-7-yl]propyl}(trihydroxy)borate(1-)


Mass: 289.156 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C12H26BN2O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 806 / 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: 2.46 Å3/Da / Density % sol: 49.98 %
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: 2.02→47.59 Å / Num. obs: 121309 / % possible obs: 93 % / Redundancy: 3.1 % / CC1/2: 0.97 / Rmerge(I) obs: 0.17 / Net I/σ(I): 5.1
Reflection shellResolution: 2.02→2.06 Å / Rmerge(I) obs: 0.49 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 5351 / CC1/2: 0.73

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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: 2.02→47.59 Å / Cor.coef. Fo:Fc: 0.751 / Cor.coef. Fo:Fc free: 0.699 / SU R Cruickshank DPI: 0.243 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.238 / SU Rfree Blow DPI: 0.187 / SU Rfree Cruickshank DPI: 0.191
RfactorNum. reflection% reflectionSelection details
Rfree0.258 6023 4.97 %RANDOM
Rwork0.23 ---
obs0.231 121305 92.5 %-
Displacement parametersBiso max: 116.99 Å2 / Biso mean: 15.95 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-5.7154 Å20 Å2-1.4479 Å2
2---13.8544 Å20 Å2
3---8.139 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: final / Resolution: 2.02→47.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14511 0 132 806 15449
Biso mean--13.26 11.55 -
Num. residues----1911
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d5205SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes312HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2169HARMONIC5
X-RAY DIFFRACTIONt_it14982HARMONIC20
X-RAY DIFFRACTIONt_nbd5SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1971SEMIHARMONIC5
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_contact18468SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d14982HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg20366HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion2.94
X-RAY DIFFRACTIONt_other_torsion16.19
LS refinement shellResolution: 2.02→2.07 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2601 376 5.08 %
Rwork0.246 7031 -
all0.2467 7407 -
obs--76.09 %
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)
10.22870.0554-0.1690.00840.18780.3254-0.01030.06180.00320.02170.0086-0.05940-0.03910.0018-0.0662-0.00010.0041-0.07-0.0458-0.023513.2004-1.321210.5633
20.26330.0583-0.31400.10220.3047-0.0023-0.01430.0117-0.00580.0072-0.01350.0111-0.0338-0.0049-0.0838-0.0078-0.0013-0.0156-0.0335-0.0349-10.9161-5.087543.18
30.2676-0.06280.36170.1998-0.10520.1284-0.0013-0.0703-0.0164-0.02030.0062-0.027-0.0263-0.0163-0.0049-0.06990.01-0.0084-0.0679-0.0588-0.0142-13.51442.391520.7876
40.0279-0.17830.35680.04560.10420.29410.00570.05350.00620.017-0.00410.01090.0031-0.0065-0.0016-0.0860.0143-0.0252-0.0326-0.0358-0.0109-37.646346.3729-11.9361
50.0360.15530.02060.3499-0.00120.0520.00130.0218-0.0468-0.00230.0037-0.02550.0555-0.036-0.0049-0.014-0.04150.0122-0.0652-0.0507-0.0211-7.6615-35.945916.6209
60.0619-0.0982-0.11210.1476-0.06030.0751-0.00160.02080.03150.02520.0113-0.041-0.0587-0.039-0.0097-0.00670.0438-0.0127-0.0931-0.04690.0032-34.435577.06214.7103
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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