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- EMDB-23293: Trimeric human Arginase 1 in complex with mAb1 - 2 hArg:3 mAb1 complex -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-23293 | |||||||||
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Title | Trimeric human Arginase 1 in complex with mAb1 - 2 hArg:3 mAb1 complex | |||||||||
![]() | Full map of 2 hARG trimers bound to 3Mab1, with better definition for one of the trimer/Fab half. | |||||||||
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Function / homology | ![]() 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 / negative regulation of type II interferon-mediated signaling pathway / urea cycle / 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 / negative regulation of type II interferon-mediated signaling pathway / urea cycle / 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 | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||
![]() | Gomez-Llorente Y / Scapin G / Palte RL | |||||||||
![]() | ![]() Title: Cryo-EM structures of inhibitory antibodies complexed with arginase 1 provide insight into mechanism of action. Authors: Rachel L Palte / Veronica Juan / Yacob Gomez-Llorente / Marc Andre Bailly / Kalyan Chakravarthy / Xun Chen / Daniel Cipriano / Ghassan N Fayad / Laurence Fayadat-Dilman / Symon Gathiaka / ...Authors: Rachel L Palte / Veronica Juan / Yacob Gomez-Llorente / Marc Andre Bailly / Kalyan Chakravarthy / Xun Chen / Daniel Cipriano / Ghassan N Fayad / Laurence Fayadat-Dilman / Symon Gathiaka / Heiko Greb / Brian Hall / Mas Handa / Mark Hsieh / Esther Kofman / Heping Lin / J Richard Miller / Nhung Nguyen / Jennifer O'Neil / Hussam Shaheen / Eric Sterner / Corey Strickland / Angie Sun / Shane Taremi / Giovanna Scapin / ![]() Abstract: Human Arginase 1 (hArg1) is a metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea, and modulates T-cell-mediated immune response. Arginase-targeted therapies have been ...Human Arginase 1 (hArg1) is a metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea, and modulates T-cell-mediated immune response. Arginase-targeted therapies have been pursued across several disease areas including immunology, oncology, nervous system dysfunction, and cardiovascular dysfunction and diseases. Currently, all published hArg1 inhibitors are small molecules usually less than 350 Da in size. Here we report the cryo-electron microscopy structures of potent and inhibitory anti-hArg antibodies bound to hArg1 which form distinct macromolecular complexes that are greater than 650 kDa. With local resolutions of 3.5 Å or better we unambiguously mapped epitopes and paratopes for all five antibodies and determined that the antibodies act through orthosteric and allosteric mechanisms. These hArg1:antibody complexes present an alternative mechanism to inhibit hArg1 activity and highlight the ability to utilize antibodies as probes in the discovery and development of peptide and small molecule inhibitors for enzymes in general. | |||||||||
History |
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Structure visualization
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 139.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 21.7 KB 21.7 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 15.5 KB | Display | ![]() |
Images | ![]() | 34.6 KB | ||
Masks | ![]() | 147.3 MB | ![]() | |
Others | ![]() ![]() | 136.8 MB 136.8 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7lexMC ![]() 7leyC ![]() 7lezC ![]() 7lf0C ![]() 7lf1C ![]() 7lf2C M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Full map of 2 hARG trimers bound to 3Mab1, with better definition for one of the trimer/Fab half. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.04 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
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Density Histograms |
-Half map: Half map B.
File | emd_23293_half_map_1.map | ||||||||||||
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Annotation | Half map B. | ||||||||||||
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Density Histograms |
-Half map: Half map A.
File | emd_23293_half_map_2.map | ||||||||||||
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Annotation | Half map A. | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Trimeric human arginase in complex with mAb1
Entire | Name: Trimeric human arginase in complex with mAb1 |
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Components |
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-Supramolecule #1: Trimeric human arginase in complex with mAb1
Supramolecule | Name: Trimeric human arginase in complex with mAb1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all Details: 2 trimers of human arginase bound to the Fab regions of 3 mAb1 molecules. |
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Molecular weight | Experimental: 427 KDa |
-Supramolecule #2: Trimeric human arginase
Supramolecule | Name: Trimeric human arginase / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Supramolecule #3: mAb1
Supramolecule | Name: mAb1 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Macromolecule #1: Arginase-1
Macromolecule | Name: Arginase-1 / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO / EC number: arginase |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 34.779879 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MSAKSRTIGI IGAPFSKGQP RGGVEEGPTV LRKAGLLEKL KEQECDVKDY GDLPFADIPN DSPFQIVKNP RSVGKASEQL AGKVAEVKK NGRISLVLGG DHSLAIGSIS GHARVHPDLG VIWVDAHTDI NTPLTTTSGN LHGQPVSFLL KELKGKIPDV P GFSWVTPC ...String: MSAKSRTIGI IGAPFSKGQP RGGVEEGPTV LRKAGLLEKL KEQECDVKDY GDLPFADIPN DSPFQIVKNP RSVGKASEQL AGKVAEVKK NGRISLVLGG DHSLAIGSIS GHARVHPDLG VIWVDAHTDI NTPLTTTSGN LHGQPVSFLL KELKGKIPDV P GFSWVTPC ISAKDIVYIG LRDVDPGEHY ILKTLGIKYF SMTEVDRLGI GKVMEETLSY LLGRKKRPIH LSFDVDGLDP SF TPATGTP VVGGLTYREG LYITEEIYKT GLLSGLDIME VNPSLGKTPE EVTRTVNTAV AITLACFGLA REGNHKPIDY LNP PK |
-Macromolecule #2: mAb1 heavy chain
Macromolecule | Name: mAb1 heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 6 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 50.269605 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: QVQLVQSGAE VKKPGASVKV SCKASGYTFT NYGISWVRQA PGQGLEWMGW ISAYNGNTNY AQKLQGRVTM TTDTSTSTAY MELRSLRSD DTAVYYCARE GAYGYRSPYH NWFDPWGQGT LVTVSSAKTT APSVYPLAPV CGDTTGSSVT LGCLVKGYFP E PVTLTWNS ...String: QVQLVQSGAE VKKPGASVKV SCKASGYTFT NYGISWVRQA PGQGLEWMGW ISAYNGNTNY AQKLQGRVTM TTDTSTSTAY MELRSLRSD DTAVYYCARE GAYGYRSPYH NWFDPWGQGT LVTVSSAKTT APSVYPLAPV CGDTTGSSVT LGCLVKGYFP E PVTLTWNS GSLSSGVHTF PAVLQSDLYT LSSSVTVTSS TWPSQSITCN VAHPASSTKV DKKIEPRGPT IKPCPPCKCP AP NLLGGPS VFIFPPKIKD VLMISLSPIV TCVVVDVSED DPDVQISWFV NNVEVHTAQT QTHREDYNST LRVVSALPIQ HQD WMSGKE FKCKVNNKDL PAPIERTISK PKGSVRAPQV YVLPPPEEEM TKKQVTLTCM VTDFMPEDIY VEWTNNGKTE LNYK NTEPV LDSDGSYFMY SKLRVEKKNW VERNSYSCSV VHEGLHNHHT TKSFSRTPGK |
-Macromolecule #3: mAb1 light chain
Macromolecule | Name: mAb1 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 6 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 23.488965 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: EIVMTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQ QHSLLPRTFG GGTKVEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS ...String: EIVMTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQ QHSLLPRTFG GGTKVEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS KDSTYSMSST LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRNEC |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Grid | Model: C-flat-1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Number grids imaged: 1 / Number real images: 1506 / Average exposure time: 6.0 sec. / Average electron dose: 45.5 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: RIGID BODY FIT |
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Output model | ![]() PDB-7lex: |