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- EMDB-24444: Mouse GITR (mGITR) with DTA-1 Fab fragment -

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Open data


ID or keywords:

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Basic information

Entry
Database: EMDB / ID: EMD-24444
TitleMouse GITR (mGITR) with DTA-1 Fab fragment
Map datamGITR with DTA-1 Fab
Sample
  • Complex: mGITR with DTA-1 Fab
    • Protein or peptide: Tumor necrosis factor receptor superfamily member 18,Enhanced green fluorescent protein
    • Protein or peptide: DTA-1 (heavy chain)
    • Protein or peptide: DTA-1 (light chain)
Function / homology
Function and homology information


TNFs bind their physiological receptors / tumor necrosis factor receptor activity / positive regulation of cell adhesion / bioluminescence / generation of precursor metabolites and energy / external side of plasma membrane / apoptotic process / negative regulation of apoptotic process / extracellular region
Similarity search - Function
Tumour necrosis factor receptor 18 / Tumour necrosis factor receptor 18, N-terminal / Tumor necrosis factor receptor / nerve growth factor receptor repeats. / TNFR/NGFR cysteine-rich region / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein
Similarity search - Domain/homology
Enhanced green fluorescent protein / Tumor necrosis factor receptor superfamily member 18
Similarity search - Component
Biological speciesMus musculus (house mouse) / Muromegalovirus G4
Methodsingle particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsMeyerson JR / He C
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Sci Adv / Year: 2022
Title: Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism.
Authors: Changhao He / Rachana R Maniyar / Yahel Avraham / Roberta Zappasodi / Radda Rusinova / Walter Newman / Heidi Heath / Jedd D Wolchok / Rony Dahan / Taha Merghoub / Joel R Meyerson /
Abstract: GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a ...GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology.
History
DepositionJul 14, 2021-
Header (metadata) releaseMar 9, 2022-
Map releaseMar 9, 2022-
UpdateMar 9, 2022-
Current statusMar 9, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.34
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.34
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7rfp
  • Surface level: 0.34
  • Imaged by UCSF Chimera
  • Download
  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7rfp
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24444.png

Downloads & links

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Map

FileDownload / File: emd_24444.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationmGITR with DTA-1 Fab
Voxel sizeX=Y=Z: 1.096 Å
Density
Contour LevelBy AUTHOR: 0.34 / Movie #1: 0.34
Minimum - Maximum-2.0556781 - 3.9750853
Average (Standard dev.)0.0005896952 (±0.04446873)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 420.86398 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0961.0961.096
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z420.864420.864420.864
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ368368368
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-2.0563.9750.001

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Supplemental data

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Sample components

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Entire : mGITR with DTA-1 Fab

EntireName: mGITR with DTA-1 Fab
Components
  • Complex: mGITR with DTA-1 Fab
    • Protein or peptide: Tumor necrosis factor receptor superfamily member 18,Enhanced green fluorescent protein
    • Protein or peptide: DTA-1 (heavy chain)
    • Protein or peptide: DTA-1 (light chain)

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Supramolecule #1: mGITR with DTA-1 Fab

SupramoleculeName: mGITR with DTA-1 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Tumor necrosis factor receptor superfamily member 18,Enhanced gre...

MacromoleculeName: Tumor necrosis factor receptor superfamily member 18,Enhanced green fluorescent protein
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Muromegalovirus G4
Molecular weightTheoretical: 54.848238 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGAWAMLYGV SMLCVLDLGQ PSVVEEPGCG PGKVQNGSGN NTRCCSLYAP GKEDCPKERC ICVTPEYHCG DPQCKICKHY PCQPGQRVE SQGDIVFGFR CVACAMGTFS AGRDGHCRLW TNCSQFGFLT MFPGNKTHNA VCIPEPLPTE QYGHLTVIFL V MAACIFFL ...String:
MGAWAMLYGV SMLCVLDLGQ PSVVEEPGCG PGKVQNGSGN NTRCCSLYAP GKEDCPKERC ICVTPEYHCG DPQCKICKHY PCQPGQRVE SQGDIVFGFR CVACAMGTFS AGRDGHCRLW TNCSQFGFLT MFPGNKTHNA VCIPEPLPTE QYGHLTVIFL V MAACIFFL TTVQLGLHIW QLRRQHMCPR ETQPFAEVQL SAEDACSFQF PEEERGEQTE EKCHLGGRWP AGLVPRGSAA AM VSKGEEL FTGVVPILVE LDGDVNGHKF SVSGEGEGDA TYGKLTLKFI CTTGKLPVPW PTLVTTLTYG VQCFSRYPDH MKQ HDFFKS AMPEGYVQER TIFFKDDGNY KTRAEVKFEG DTLVNRIELK GIDFKEDGNI LGHKLEYNYN SHNVYIMADK QKNG IKVNF KIRHNIEDGS VQLADHYQQN TPIGDGPVLL PDNHYLSTQS KLSKDPNEKR DHMVLLEFVT AAGITLGMDE LYKSG LRHH HHHHHH

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Macromolecule #2: DTA-1 (heavy chain)

MacromoleculeName: DTA-1 (heavy chain) / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 51.014621 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGWSCIILFL VATATGVHSE LQLVESGGGL VQPGRSLKLS CSASGFIFSN SYMAWVRQAP KKGLEWVATI NPSGSRTYYP DSVKGRFTI SRDTAKSSLY LQMNSLKSED TATYYCARHD LSFDYWGQGV MVTVSSASTK GPSVFPLAPS SKSTSGGTAA L GCLVKDYF ...String:
MGWSCIILFL VATATGVHSE LQLVESGGGL VQPGRSLKLS CSASGFIFSN SYMAWVRQAP KKGLEWVATI NPSGSRTYYP DSVKGRFTI SRDTAKSSLY LQMNSLKSED TATYYCARHD LSFDYWGQGV MVTVSSASTK GPSVFPLAPS SKSTSGGTAA L GCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DK THTCPPC PAPELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST YRV VSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWE SNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK

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Macromolecule #3: DTA-1 (light chain)

MacromoleculeName: DTA-1 (light chain) / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.320057 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGWSCIILFL VATATGVHSQ FTLTQPKSVS GSLRSTITIP CDRSSGGIRD SYVSWYQQHL GRPPLNVIYA DDQRPSEVSD RFSGSIDSS SNSASLTITN LQMDDEADYF CQSYDSDFDV YIFGGGTKLT VLGQRTVAAP SVFIFPPSDE QLKSGTASVV C LLNNFYPR ...String:
MGWSCIILFL VATATGVHSQ FTLTQPKSVS GSLRSTITIP CDRSSGGIRD SYVSWYQQHL GRPPLNVIYA DDQRPSEVSD RFSGSIDSS SNSASLTITN LQMDDEADYF CQSYDSDFDV YIFGGGTKLT VLGQRTVAAP SVFIFPPSDE QLKSGTASVV C LLNNFYPR EAKVQWKVDN ALQSGNSQES VTEQDSKDST YSLSSTLTLS KADYEKHKVY ACEVTHQGLS SPVTKSFNRG EC

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 423425
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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