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- EMDB-23294: Trimeric human Arginase 1 in complex with mAb5 -

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Basic information

Entry
Database: EMDB / ID: EMD-23294
TitleTrimeric human Arginase 1 in complex with mAb5
Map dataFull map of 2x3hArg:3Mab5
Sample
  • Complex: Trimeric human arginase in complex with mAb5
    • Complex: Arginase-1
      • Protein or peptide: Arginase-1
    • Complex: mAb5
      • Protein or peptide: mAb5 heavy chain
      • Protein or peptide: mAb5 light chain
  • Ligand: MANGANESE (II) ION
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 / arginase activity / arginine catabolic process to ornithine / 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 / arginase activity / arginine catabolic process to ornithine / 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 / cytoplasm / cytosol
Similarity search - Function
Arginase / Ureohydrolase, manganese-binding site / Arginase family signature. / Ureohydrolase / Arginase family / Arginase family profile. / Ureohydrolase domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.05 Å
AuthorsGomez-Llorente Y / Scapin G / Palte RL
CitationJournal: Commun Biol / Year: 2021
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
DepositionJan 15, 2021-
Header (metadata) releaseSep 1, 2021-
Map releaseSep 1, 2021-
UpdateSep 1, 2021-
Current statusSep 1, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.45
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.45
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7ley
  • Surface level: 0.45
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23294.png

Downloads & links

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Map

FileDownload / File: emd_23294.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map of 2x3hArg:3Mab5
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 0.25 / Movie #1: 0.45
Minimum - Maximum-1.5216649 - 3.121146
Average (Standard dev.)0.008597111 (±0.07092048)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 332.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z332.800332.800332.800
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-1.5223.1210.009

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Supplemental data

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Mask #1

Fileemd_23294_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B.

Fileemd_23294_half_map_1.map
AnnotationHalf map B.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A.

Fileemd_23294_half_map_2.map
AnnotationHalf map A.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Trimeric human arginase in complex with mAb5

EntireName: Trimeric human arginase in complex with mAb5
Components
  • Complex: Trimeric human arginase in complex with mAb5
    • Complex: Arginase-1
      • Protein or peptide: Arginase-1
    • Complex: mAb5
      • Protein or peptide: mAb5 heavy chain
      • Protein or peptide: mAb5 light chain
  • Ligand: MANGANESE (II) ION

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Supramolecule #1: Trimeric human arginase in complex with mAb5

SupramoleculeName: Trimeric human arginase in complex with mAb5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: 2 trimers of human arginase, bound to 3 mAb5 molecules
Molecular weightExperimental: 427 KDa

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Supramolecule #2: Arginase-1

SupramoleculeName: Arginase-1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli) / Recombinant strain: 'BL21-Gold(DE3)pLysS AG'

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Supramolecule #3: mAb5

SupramoleculeName: mAb5 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)

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Macromolecule #1: Arginase-1

MacromoleculeName: Arginase-1 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO / EC number: arginase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.779879 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: 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

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Macromolecule #2: mAb5 heavy chain

MacromoleculeName: mAb5 heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.036074 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EVQLVESGGG VVRPGGSLRL SCAASGFTFD DYGMTWVRQA PGKGLEWVSG INWNGGSTGY ADSVKGRFTI SRDNAKNSLY LQMNSLRAE DTALYHCARD RRRGSYGSDA FDIWGQGTMV TVSSAKTTPP SVYPLAPGSA AQTNSMVTLG CLVKGYFPEP V TVTWNSGS ...String:
EVQLVESGGG VVRPGGSLRL SCAASGFTFD DYGMTWVRQA PGKGLEWVSG INWNGGSTGY ADSVKGRFTI SRDNAKNSLY LQMNSLRAE DTALYHCARD RRRGSYGSDA FDIWGQGTMV TVSSAKTTPP SVYPLAPGSA AQTNSMVTLG CLVKGYFPEP V TVTWNSGS LSSGVHTFPA VLESDLYTLS SSVTVPSSPR PSETVTCNVA HPASSTKVDK KIVPRDCGCK PCICTVPEVS SV FIFPPKP KDVLTITLTP KVTCVVVDIS KDDPEVQFSW FVDDVEVHTA QTQPREEQFN STFRSVSELP IMHQDWLNGK EFK CRVNSA AFPAPIEKTI SKTKGRPKAP QVYTIPPPKE QMAKDKVSLT CMITDFFPED ITVEWQWNGQ PAENYKNTQP IMNT NGSYF VYSKLNVQKS NWEAGNTFTC SVLHEGLHNH HTEKSLSHSP GK

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Macromolecule #3: mAb5 light chain

MacromoleculeName: mAb5 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.381787 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQGIS NYLAWYQQKP GKVPQLLISA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQ KYNSAPRTFG QGTKVEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQGIS NYLAWYQQKP GKVPQLLISA ASTLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCQ KYNSAPRTFG QGTKVEIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK IDGSERQNGV L NSWTDQDS KDSTYSMSST LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRNEC

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Macromolecule #4: MANGANESE (II) ION

MacromoleculeName: MANGANESE (II) ION / type: ligand / ID: 4 / Number of copies: 6 / Formula: MN
Molecular weightTheoretical: 54.938 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm 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: 1197 / Average exposure time: 6.0 sec. / Average electron dose: 44.3 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Sample stageSpecimen 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

CTF correctionSoftware - Name: cryoSPARC (ver. 2.0.23)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.0.23) / Number images used: 44345
Initial angle assignmentType: OTHER / Software - Name: cryoSPARC (ver. 2.0.23)
Final angle assignmentType: OTHER / Software - Name: cryoSPARC (ver. 2.0.23)
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC (ver. 2.0.23)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-7ley:
Trimeric human Arginase 1 in complex with mAb5

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