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- PDB-8rew: CryoEM structure of human GARP-lTGFbeta1 in complex with a Fab fr... -

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Basic information

Entry
Database: PDB / ID: 8rew
TitleCryoEM structure of human GARP-lTGFbeta1 in complex with a Fab fragment derived from an activating antibody.
Components
  • (Transforming growth factor ...) x 2
  • (hFab LHT-22, ...) x 2
KeywordsIMMUNE SYSTEM / GARP / TGF-B1 / ACTIVATION / TREG / ANTIBODY
Function / homology
Function and homology information


establishment of protein localization to extracellular region / cellular response to acetaldehyde / 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 / branch elongation involved in mammary gland duct branching / positive regulation of primary miRNA processing / Influenza Virus Induced Apoptosis / regulation of branching involved in mammary gland duct morphogenesis / negative regulation of skeletal muscle tissue development ...establishment of protein localization to extracellular region / cellular response to acetaldehyde / 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 / branch elongation involved in mammary gland duct branching / positive regulation of primary miRNA processing / Influenza Virus Induced Apoptosis / regulation of branching involved in mammary gland duct morphogenesis / negative regulation of skeletal muscle tissue development / macrophage derived foam cell differentiation / frontal suture morphogenesis / regulation of enamel mineralization / regulation of cartilage development / TGFBR2 MSI Frameshift Mutants in Cancer / regulation of striated muscle tissue development / regulatory T cell differentiation / tolerance induction to self antigen / regulation of blood vessel remodeling / regulation of protein import into nucleus / embryonic liver development / extracellular matrix assembly / columnar/cuboidal epithelial cell maturation / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / negative regulation of hyaluronan biosynthetic process / type III transforming growth factor beta receptor binding / positive regulation of cardiac muscle cell differentiation / myofibroblast differentiation / odontoblast differentiation / connective tissue replacement involved in inflammatory response wound healing / positive regulation of odontogenesis / Langerhans cell differentiation / negative regulation of macrophage cytokine production / positive regulation of exit from mitosis / positive regulation of smooth muscle cell differentiation / TGFBR2 Kinase Domain Mutants in Cancer / positive regulation of isotype switching to IgA isotypes / secondary palate development / positive regulation of mesenchymal stem cell proliferation / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / mammary gland branching involved in thelarche / membrane protein intracellular domain proteolysis / positive regulation of receptor signaling pathway via STAT / retina vasculature development in camera-type eye / heart valve morphogenesis / TGFBR3 regulates TGF-beta signaling / bronchiole development / response to laminar fluid shear stress / hyaluronan catabolic process / positive regulation of vasculature development / lens fiber cell differentiation / positive regulation of extracellular matrix assembly / ATP biosynthetic process / receptor catabolic process / negative regulation of extracellular matrix disassembly / positive regulation of branching involved in ureteric bud morphogenesis / type II transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / negative regulation of biomineral tissue development / response to salt / oligodendrocyte development / type I transforming growth factor beta receptor binding / receptor ligand inhibitor activity / germ cell migration / positive regulation of mononuclear cell migration / positive regulation of chemotaxis / endoderm development / phospholipid homeostasis / negative regulation of myoblast differentiation / negative regulation of cell-cell adhesion mediated by cadherin / cell-cell junction organization / response to vitamin D / response to cholesterol / positive regulation of vascular permeability / negative regulation of interleukin-17 production / surfactant homeostasis / deubiquitinase activator activity / transforming growth factor beta binding / negative regulation of release of sequestered calcium ion into cytosol / digestive tract development / positive regulation of chemokine (C-X-C motif) ligand 2 production / phosphate-containing compound metabolic process / aortic valve morphogenesis / positive regulation of fibroblast migration / negative regulation of ossification / sprouting angiogenesis / RUNX3 regulates CDKN1A transcription / face morphogenesis / neural tube development / positive regulation of regulatory T cell differentiation / negative regulation of phagocytosis / negative regulation of cytokine production / ureteric bud development / Molecules associated with elastic fibres / positive regulation of epidermal growth factor receptor signaling pathway / negative regulation of neuroblast proliferation / muscle cell cellular homeostasis / ventricular cardiac muscle tissue morphogenesis / Syndecan interactions
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 / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain ...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 / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / 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, 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
Similarity search - Domain/homology
Transforming growth factor beta-1 proprotein / Transforming growth factor beta activator LRRC32
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsFelix, J. / Lambert, F. / Marien, L. / van der Woning, B. / Savvides, S.N. / Lucas, S.
Funding support Belgium, 5items
OrganizationGrant numberCountry
Other privateFondation contre le Cancer / 2020-079
Other governmentARC / 19/24-098 Belgium
Fonds National de la Recherche Scientifique (FNRS)PDR / T.0145.21 Belgium
Fonds National de la Recherche Scientifique (FNRS)WELBIO / CR2019A-02R Belgium
Other privateSalus Sanguinis
CitationJournal: To Be Published
Title: TGF-beta1 activating antibodies as novel immunotherapeutics for graft-versus-host disease.
Authors: Lambert, F. / Felix, J. / Wautier, S. / Gaignage, M. / Dupre, E. / Marien, L. / Lesage, M. / van der Woning, B. / Coulie, P.G. / Savvides, S.N. / Lucas, S.
History
DepositionDec 12, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 26, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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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
E: Transforming growth factor beta activator LRRC32
F: hFab LHT-22, Light Chain
G: hFab LHT-22, Heavy Chain
H: hFab LHT-22, Heavy Chain
I: hFab LHT-22, Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)356,56717
Polymers353,5399
Non-polymers3,0288
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area25270 Å2
ΔGint-67 kcal/mol
Surface area65600 Å2
MethodPISA

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Components

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Transforming growth factor ... , 2 types, 5 molecules ABCDE

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


Mass: 44383.051 Da / Num. of mol.: 4 / 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 activator LRRC32 / Garpin / Glycoprotein A repetitions predominant / GARP / Leucine-rich repeat-containing protein 32


Mass: 73261.523 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

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Antibody , 2 types, 4 molecules FIGH

#3: Antibody hFab LHT-22, Light Chain


Mass: 25104.023 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Homo sapiens (human)
#4: Antibody hFab LHT-22, Heavy Chain


Mass: 26268.613 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Homo sapiens (human)

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Sugars , 3 types, 8 molecules

#5: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#6: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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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: human GAPR-lTGFbeta1 in complex with Fab LHT-22. / Type: COMPLEX / Entity ID: #2-#4 / Source: RECOMBINANT
Molecular weightValue: 260 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMHEPESC8H18N2O4S1
2150 mMsodium chlorideNaCl1
SpecimenConc.: 0.13 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: Grids were acquired via PUXANO (https://puxano.com)
Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingAverage exposure time: 3.37 sec. / Electron dose: 61.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 13898
Details: A total of 6678 untilted movies were collected with a defocus of 0.8 to 2 micrometer. Following untilted data collection, 4020 movies were collected at 16 degree tilt and 3200 movies were ...Details: A total of 6678 untilted movies were collected with a defocus of 0.8 to 2 micrometer. Following untilted data collection, 4020 movies were collected at 16 degree tilt and 3200 movies were collected at 35 degree tilt, all using similar microscope settings.

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Processing

EM software
IDNameVersionCategory
2SerialEMimage acquisition
4cryoSPARC4.2.1CTF correction
7UCSF Chimeramodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIX1.19.2-4158model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 320551 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 6GFF

6gff


Accession code: 6GFF / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00412682
ELECTRON MICROSCOPYf_angle_d0.73517270
ELECTRON MICROSCOPYf_dihedral_angle_d5.741840
ELECTRON MICROSCOPYf_chiral_restr0.0462032
ELECTRON MICROSCOPYf_plane_restr0.0072199

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