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- PDB-7rfp: Mouse GITR (mGITR) with DTA-1 Fab fragment -

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Basic information

Entry
Database: PDB / ID: 7rfp
TitleMouse GITR (mGITR) with DTA-1 Fab fragment
Components
  • DTA-1 (heavy chain)
  • DTA-1 (light chain)
  • Tumor necrosis factor receptor superfamily member 18,Enhanced green fluorescent protein
KeywordsIMMUNE SYSTEM / Mouse glucocorticoid-induced tumor necrosis factor receptor / mGITR / TNF receptor / DTA-1
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 / negative regulation of apoptotic process / 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
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsMeyerson, J.R. / He, C.
Funding support1items
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Tumor necrosis factor receptor superfamily member 18,Enhanced green fluorescent protein
B: Tumor necrosis factor receptor superfamily member 18,Enhanced green fluorescent protein
H: DTA-1 (heavy chain)
L: DTA-1 (light chain)
I: DTA-1 (heavy chain)
M: DTA-1 (light chain)


Theoretical massNumber of molelcules
Total (without water)264,3666
Polymers264,3666
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Tumor necrosis factor receptor superfamily member 18,Enhanced green fluorescent protein / Glucocorticoid-induced TNFR-related protein


Mass: 54848.238 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse), (gene. exp.) Muromegalovirus G4
Gene: Tnfrsf18, Gitr, eGFP / Production host: Homo sapiens (human) / References: UniProt: O35714, UniProt: A0A7G8ZY66
#2: Antibody DTA-1 (heavy chain)


Mass: 51014.621 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Antibody DTA-1 (light chain)


Mass: 26320.057 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: mGITR with DTA-1 Fab / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 423425 / Symmetry type: POINT

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