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- EMDB-16460: Cryo-EM Map of the latTGF-beta 28G11 Fab complex -

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Basic information

Entry
Database: EMDB / ID: EMD-16460
TitleCryo-EM Map of the latTGF-beta 28G11 Fab complex
Map dataSharpened map
Sample
  • Complex: latTGF-beta in complex with Fab 28G11
  • Protein or peptide: Transforming growth factor beta-1
  • Protein or peptide: Transforming growth factor beta-1
  • Protein or peptide: Transforming growth factor beta activator LRRC32
  • Protein or peptide: 28G11 Fab heavy chain
  • Protein or peptide: 28G11 Fab light chain
Function / homology
Function and homology information


: / 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 / Influenza Virus Induced Apoptosis / regulation of branching involved in mammary gland duct morphogenesis / frontal suture morphogenesis / negative regulation of skeletal muscle tissue development / TGFBR2 MSI Frameshift Mutants in Cancer ...: / 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 / Influenza Virus Induced Apoptosis / regulation of branching involved in mammary gland duct morphogenesis / frontal suture morphogenesis / negative regulation of skeletal muscle tissue development / TGFBR2 MSI Frameshift Mutants in Cancer / regulation of enamel mineralization / regulatory T cell differentiation / regulation of cartilage development / regulation of blood vessel remodeling / regulation of striated muscle tissue development / tolerance induction to self antigen / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / regulation of protein import into nucleus / embryonic liver development / columnar/cuboidal epithelial cell maturation / type III transforming growth factor beta receptor binding / negative regulation of hyaluronan biosynthetic process / Langerhans cell differentiation / positive regulation of odontogenesis / positive regulation of cardiac muscle cell differentiation / myofibroblast differentiation / connective tissue replacement involved in inflammatory response wound healing / extracellular matrix assembly / positive regulation of exit from mitosis / negative regulation of macrophage cytokine production / positive regulation of receptor signaling pathway via STAT / odontoblast differentiation / TGFBR2 Kinase Domain Mutants in Cancer / : / positive regulation of smooth muscle cell differentiation / positive regulation of mesenchymal stem cell proliferation / positive regulation of isotype switching to IgA isotypes / secondary palate development / mammary gland branching involved in thelarche / membrane protein intracellular domain proteolysis / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / heart valve morphogenesis / response to laminar fluid shear stress / positive regulation of primary miRNA processing / retina vasculature development in camera-type eye / positive regulation of vasculature development / hyaluronan catabolic process / bronchiole development / regulation of transforming growth factor beta receptor signaling pathway / ATP biosynthetic process / receptor catabolic process / positive regulation of branching involved in ureteric bud morphogenesis / negative regulation of extracellular matrix disassembly / positive regulation of extracellular matrix assembly / lens fiber cell differentiation / type II transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / oligodendrocyte development / germ cell migration / response to salt / negative regulation of biomineral tissue development / type I transforming growth factor beta receptor binding / positive regulation of chemotaxis / phospholipid homeostasis / endoderm development / negative regulation of myoblast differentiation / positive regulation of mononuclear cell migration / response to vitamin D / cell-cell junction organization / positive regulation of vascular permeability / positive regulation of regulatory T cell differentiation / response to cholesterol / transforming growth factor beta binding / digestive tract development / positive regulation of endothelial cell apoptotic process / negative regulation of interleukin-17 production / deubiquitinase activator activity / surfactant homeostasis / negative regulation of release of sequestered calcium ion into cytosol / positive regulation of fibroblast migration / negative regulation of ossification / positive regulation of chemokine (C-X-C motif) ligand 2 production / aortic valve morphogenesis / phosphate-containing compound metabolic process / negative regulation of phagocytosis / negative regulation of protein localization to plasma membrane / sprouting angiogenesis / neural tube development / face morphogenesis / Molecules associated with elastic fibres / RUNX3 regulates CDKN1A transcription / negative regulation of cytokine production / ureteric bud development / cellular response to insulin-like growth factor stimulus / ventricular cardiac muscle tissue morphogenesis / positive regulation of epidermal growth factor receptor signaling pathway / macrophage derived foam cell differentiation / negative regulation of neuroblast proliferation / 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. / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsEbenhoch R / Nar H
Funding support1 items
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, 2023-
Header (metadata) releaseMar 1, 2023-
Map releaseMar 1, 2023-
UpdateMar 29, 2023-
Current statusMar 29, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16460.png

Downloads & links

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Map

FileDownload / File: emd_16460.map.gz / Format: CCP4 / Size: 8.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.624
Minimum - Maximum-3.6561434 - 4.836684
Average (Standard dev.)1.0530627e-12 (±0.18210551)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin966398
Dimensions125172108
Spacing108125172
CellA: 116.64001 Å / B: 135.0 Å / C: 185.76001 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map B

Fileemd_16460_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_16460_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 : latTGF-beta in complex with Fab 28G11

EntireName: latTGF-beta in complex with Fab 28G11
Components
  • Complex: latTGF-beta in complex with Fab 28G11
  • Protein or peptide: Transforming growth factor beta-1
  • Protein or peptide: Transforming growth factor beta-1
  • Protein or peptide: Transforming growth factor beta activator LRRC32
  • Protein or peptide: 28G11 Fab heavy chain
  • Protein or peptide: 28G11 Fab light chain

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Supramolecule #1: latTGF-beta in complex with Fab 28G11

SupramoleculeName: latTGF-beta in complex with Fab 28G11 / type: complex / ID: 1 / Chimera: Yes / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transforming growth factor beta-1

MacromoleculeName: Transforming growth factor beta-1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.531488 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LSTCKTIDME LVKRKRIEAI RGQILSKLRL ASPPSQGEVP PGPLPEAVLA LYNSTRDRVA GESAEPEPEP EADYYAKEVT RVLMVETHN EIYDKFKQST HSIYMFFNTS ELREAVPEPV LLSRAELRLL RLKLKVEQHV ELYQKYSNNS WRYLSNRLLA P SDSPEWLS ...String:
LSTCKTIDME LVKRKRIEAI RGQILSKLRL ASPPSQGEVP PGPLPEAVLA LYNSTRDRVA GESAEPEPEP EADYYAKEVT RVLMVETHN EIYDKFKQST HSIYMFFNTS ELREAVPEPV LLSRAELRLL RLKLKVEQHV ELYQKYSNNS WRYLSNRLLA P SDSPEWLS FDVTGVVRQW LSRGGEIEGF RLSAHCSCDS RDNTLQVDIN GFTTGRRGDL ATIHGMNRPF LLLMATPLER AQ HLQSSRH RR

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Macromolecule #2: Transforming growth factor beta-1

MacromoleculeName: Transforming growth factor beta-1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.809812 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
ALDTNYCFSS TEKNCCVRQL YIDFRKDLGW KWIHEPKGYH ANFCLGPCPY IWSLDTQYSK VLALYNQHNP GASAAPCCVP QALEPLPIV YYVGRKPKVE QLSNMIVRSC KCS

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Macromolecule #3: Transforming growth factor beta activator LRRC32

MacromoleculeName: Transforming growth factor beta activator LRRC32 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 65.358488 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: HQDKVPCKMV DKKVSCQVLG LLQVPSVLPP DTETLDLSGN QLRSILASPL GFYTALRHLD LSTNEISFLQ PGAFQALTHL EHLSLAHNR LAMATALSAG GLGPLPRVTS LDLSGNSLYS GLLERLLGEA PSLHTLSLAE NSLTRLTRHT FRDMPALEQL D LHSNVLMD ...String:
HQDKVPCKMV DKKVSCQVLG LLQVPSVLPP DTETLDLSGN QLRSILASPL GFYTALRHLD LSTNEISFLQ PGAFQALTHL EHLSLAHNR LAMATALSAG GLGPLPRVTS LDLSGNSLYS GLLERLLGEA PSLHTLSLAE NSLTRLTRHT FRDMPALEQL D LHSNVLMD IEDGAFEGLP RLTHLNLSRN SLTCISDFSL QQLRVLDLSC NSIEAFQTAS QPQAEFQLTW LDLRENKLLH FP DLAALPR LIYLNLSNNL IRLPTGPPQD SKGIHAPSEG WSALPLSAPS GNASGRPLSQ LLNLDLSYNE IELIPDSFLE HLT SLCFLN LSRNCLRTFE ARRLGSLPCL MLLDLSHNAL ETLELGARAL GSLRTLLLQG NALRDLPPYT FANLASLQRL NLQG NRVSP CGGPDEPGPS GCVAFSGITS LRSLSLVDNE IELLRAGAFL HTPLTELDLS SNPGLEVATG ALGGLEASLE VLALQ GNGL MVLQVDLPCF ICLKRLNLAE NRLSHLPAWT QAVSLEVLDL RNNSFSLLPG SAMGGLETSL RRLYLQGNPL SCCGNG WLA AQLHQGRVDV DATQDLICRF SSQEEVSLSH VRPEDCEK

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Macromolecule #4: 28G11 Fab heavy chain

MacromoleculeName: 28G11 Fab heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.529211 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVQPGAE LRNSGASVKV SCKASGYRFT SYYIDWVRQA PGQGLEWMGR IDPEDGGTKY AQKFQGRVTF TADTSTSTAY VELSSLRSE DTAVYYCARN EWETVVVGDL MYEYEYWGQG TQVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF P EPVTVSWN ...String:
EVQLVQPGAE LRNSGASVKV SCKASGYRFT SYYIDWVRQA PGQGLEWMGR IDPEDGGTKY AQKFQGRVTF TADTSTSTAY VELSSLRSE DTAVYYCARN EWETVVVGDL MYEYEYWGQG TQVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF P EPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKRVEPK

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Macromolecule #5: 28G11 Fab light chain

MacromoleculeName: 28G11 Fab light chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.091578 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS LSASLGDRVT ITCQASQSIS SYLAWYQQKP GQAPNILIYG ASRLKTGVPS RFSGSGSGTS FTLTISGLEA EDAGTYYCQ QYASVPVTFG QGTKVELKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS LSASLGDRVT ITCQASQSIS SYLAWYQQKP GQAPNILIYG ASRLKTGVPS RFSGSGSGTS FTLTISGLEA EDAGTYYCQ QYASVPVTFG QGTKVELKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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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: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 80 % / Chamber temperature: 4 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6gff

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 418886

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