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- PDB-8c7h: Cryo-EM Map of the latTGF-beta LHG-10 Fab complex -

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Basic information

Entry
Database: PDB / ID: 8c7h
TitleCryo-EM Map of the latTGF-beta LHG-10 Fab complex
Components
  • (Transforming growth factor beta- ...) x 2
  • 28G11 Fab heavy chain
  • 28G11 Fab light chain
  • Transforming growth factor beta activator LRRC32
KeywordsIMMUNE SYSTEM / Fab-complex / GARP / lat-TGF-beta
Function / homology
Function and homology information


establishment of protein localization to extracellular region / columnar/cuboidal epithelial cell maturation / branch elongation involved in mammary gland duct branching / frontal suture morphogenesis / Influenza Virus Induced Apoptosis / adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains / positive regulation of microglia differentiation / regulation of interleukin-23 production / positive regulation of primary miRNA processing / negative regulation of skeletal muscle tissue development ...establishment of protein localization to extracellular region / columnar/cuboidal epithelial cell maturation / branch elongation involved in mammary gland duct branching / frontal suture morphogenesis / Influenza Virus Induced Apoptosis / adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains / positive regulation of microglia differentiation / regulation of interleukin-23 production / positive regulation of primary miRNA processing / negative regulation of skeletal muscle tissue development / response to laminar fluid shear stress / regulation of enamel mineralization / embryonic liver development / regulation of cartilage development / macrophage derived foam cell differentiation / regulation of branching involved in mammary gland duct morphogenesis / TGFBR2 MSI Frameshift Mutants in Cancer / regulation of striated muscle tissue development / regulation of protein import into nucleus / regulation of blood vessel remodeling / tolerance induction to self antigen / cellular response to acetaldehyde / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / extracellular matrix assembly / negative regulation of hyaluronan biosynthetic process / type III transforming growth factor beta receptor binding / myofibroblast differentiation / positive regulation of odontogenesis / Langerhans cell differentiation / connective tissue replacement involved in inflammatory response wound healing / TGFBR2 Kinase Domain Mutants in Cancer / positive regulation of smooth muscle cell differentiation / positive regulation of exit from mitosis / negative regulation of macrophage cytokine production / secondary palate development / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / odontoblast differentiation / positive regulation of mesenchymal stem cell proliferation / positive regulation of receptor signaling pathway via STAT / positive regulation of isotype switching to IgA isotypes / membrane protein intracellular domain proteolysis / bronchiole development / retina vasculature development in camera-type eye / positive regulation of extracellular matrix assembly / mammary gland branching involved in thelarche / heart valve morphogenesis / lens fiber cell differentiation / TGFBR3 regulates TGF-beta signaling / positive regulation of vasculature development / hyaluronan catabolic process / ATP biosynthetic process / negative regulation of extracellular matrix disassembly / type II transforming growth factor beta receptor binding / positive regulation of branching involved in ureteric bud morphogenesis / receptor catabolic process / positive regulation of cardiac muscle cell differentiation / TGFBR1 LBD Mutants in Cancer / primordial germ cell migration / regulatory T cell differentiation / response to salt / endoderm development / receptor ligand inhibitor activity / negative regulation of cell-cell adhesion mediated by cadherin / negative regulation of myoblast differentiation / phospholipid homeostasis / positive regulation of mononuclear cell migration / negative regulation of biomineral tissue development / type I transforming growth factor beta receptor binding / positive regulation of chemotaxis / positive regulation of vascular permeability / negative regulation of interleukin-17 production / phosphate-containing compound metabolic process / response to cholesterol / cell-cell junction organization / oligodendrocyte development / surfactant homeostasis / transforming growth factor beta binding / sprouting angiogenesis / positive regulation of chemokine (C-X-C motif) ligand 2 production / negative regulation of ossification / aortic valve morphogenesis / RUNX3 regulates CDKN1A transcription / response to vitamin D / digestive tract development / face morphogenesis / neural tube development / positive regulation of fibroblast migration / ureteric bud development / negative regulation of release of sequestered calcium ion into cytosol / positive regulation of regulatory T cell differentiation / Molecules associated with elastic fibres / negative regulation of neuroblast proliferation / negative regulation of cytokine production / lung alveolus development / muscle cell cellular homeostasis / Syndecan interactions / cellular response to insulin-like growth factor stimulus / ventricular cardiac muscle tissue morphogenesis / negative regulation of activated T cell proliferation
Similarity search - Function
Transforming growth factor beta-1 proprotein / Transforming growth factor-beta / Leucine rich repeat N-terminal domain / TGF-beta, propeptide / TGF-beta propeptide / Transforming growth factor beta, conserved site / TGF-beta family signature. / Transforming growth factor-beta-related / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal ...Transforming growth factor beta-1 proprotein / Transforming growth factor-beta / Leucine rich repeat N-terminal domain / TGF-beta, propeptide / TGF-beta propeptide / Transforming growth factor beta, conserved site / TGF-beta family signature. / Transforming growth factor-beta-related / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Leucine rich repeat, ribonuclease inhibitor type / Leucine-rich repeats, bacterial type / Cystine-knot cytokine / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Transforming growth factor beta-1 proprotein / Transforming growth factor beta activator LRRC32
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsEbenhoch, R. / Nar, H.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Immunohorizons / Year: 2023
Title: Anti-GARP Antibodies Inhibit Release of TGF-β by Regulatory T Cells via Different Modes of Action, but Do Not Influence Their Function In Vitro.
Authors: Frederik H Igney / Rebecca Ebenhoch / Felix Schiele / Herbert Nar /
Abstract: Regulatory T cells (Treg) play a critical role in controlling immune responses in diseases such as cancer or autoimmunity. Activated Treg express the membrane protein GARP (LRRC32) in complex with ...Regulatory T cells (Treg) play a critical role in controlling immune responses in diseases such as cancer or autoimmunity. Activated Treg express the membrane protein GARP (LRRC32) in complex with the latent form of the immunosuppressive cytokine TGF-β (L-TGF-β). In this study, we confirmed that active TGF-β was generated from its latent form in an integrin-dependent manner and induced TGF-β receptor signaling in activated human Treg. We studied a series of Abs targeting the L-TGF-β/GARP complex with distinct binding modes. We found that TGF-β receptor signaling could be inhibited by anti-TGF-β and by some, but not all, Abs against the L-TGF-β/GARP complex. Cryogenic electron microscopy structures of three L-TGF-β/GARP complex-targeting Abs revealed their distinct epitopes and allowed us to elucidate how they achieve blockade of TGF-β activation. Three different modes of action were identified, including a novel unusual mechanism of a GARP-binding Ab. However, blockade of GARP or TGF-β by Abs did not influence the suppressive activity of human Treg in vitro. We were also not able to confirm a prominent role of GARP in other functions of human Treg, such as FOXP3 induction and Treg stability. These data show that the GARP/TGF-β axis can be targeted pharmacologically in different ways, but further studies are necessary to understand its complexity and to unleash its therapeutic potential.
History
DepositionJan 16, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 1, 2023Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 1, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 29, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 9, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3Nov 6, 2024Group: Data collection / Structure summary / Category: em_admin / struct
Item: _em_admin.last_update / _em_admin.title / _struct.title
Revision 1.4Jul 9, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 9, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transforming growth factor beta-1
B: Transforming growth factor beta-1
C: Transforming growth factor beta-1
D: Transforming growth factor beta-1
I: Transforming growth factor beta activator LRRC32
L: 28G11 Fab heavy chain
K: 28G11 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)197,42210
Polymers195,6627
Non-polymers1,7603
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area18620 Å2
ΔGint-68 kcal/mol
Surface area57000 Å2

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Components

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Transforming growth factor beta- ... , 2 types, 4 molecules ACBD

#1: Protein Transforming growth factor beta-1 / TGF-beta-1


Mass: 28531.488 Da / Num. of mol.: 2 / Fragment: LAP
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFB1, TGFB / Production host: Homo sapiens (human) / References: UniProt: P01137
#2: Protein Transforming growth factor beta-1 / TGF-beta-1


Mass: 12809.812 Da / Num. of mol.: 2 / Fragment: Mature
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFB1, TGFB / Production host: Homo sapiens (human) / References: UniProt: P01137

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Antibody , 2 types, 2 molecules LK

#4: Antibody 28G11 Fab heavy chain


Mass: 24529.211 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody 28G11 Fab light chain


Mass: 23091.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Protein / Sugars , 2 types, 4 molecules I

#3: Protein Transforming growth factor beta activator LRRC32 / Garpin / Glycoprotein A repetitions predominant / GARP / Leucine-rich repeat-containing protein 32


Mass: 65358.488 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LRRC32, D11S833E / Production host: Homo sapiens (human) / References: UniProt: Q14392
#6: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE

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Details

Has ligand of interestN
Has protein modificationY

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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: latTGF-beta in complex with Fab 28G11 / Type: COMPLEX / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK293
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 80 % / Chamber temperature: 4 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: dev_4839: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 418886 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00411889
ELECTRON MICROSCOPYf_angle_d0.67916246
ELECTRON MICROSCOPYf_dihedral_angle_d4.4621750
ELECTRON MICROSCOPYf_chiral_restr0.0421944
ELECTRON MICROSCOPYf_plane_restr0.0092095

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