6UJA

Integrin alpha-v beta-8 in complex with pro-TGF-beta1


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.30 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

Cryo-EM Reveals Integrin-Mediated TGF-beta Activation without Release from Latent TGF-beta.

Campbell, M.G.Cormier, A.Ito, S.Seed, R.I.Bondesson, A.J.Lou, J.Marks, J.D.Baron, J.L.Cheng, Y.Nishimura, S.L.

(2020) Cell 180: 490

  • DOI: https://doi.org/10.1016/j.cell.2019.12.030
  • Primary Citation of Related Structures:  
    6UJA, 6UJB, 6UJC

  • PubMed Abstract: 

    Integrin αvβ8 binds with exquisite specificity to latent transforming growth factor-β (L-TGF-β). This binding is essential for activating L-TGF-β presented by a variety of cell types. Inhibiting αvβ8-mediated TGF-β activation blocks immunosuppressive regulatory T cell differentiation, which is a potential therapeutic strategy in cancer. Using cryo-electron microscopy, structure-guided mutagenesis, and cell-based assays, we reveal the binding interactions between the entire αvβ8 ectodomain and its intact natural ligand, L-TGF-β, as well as two different inhibitory antibody fragments to understand the structural underpinnings of αvβ8 binding specificity and TGF-β activation. Our studies reveal a mechanism of TGF-β activation where mature TGF-β signals within the confines of L-TGF-β and the release and diffusion of TGF-β are not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit αvβ8-mediated L-TGF-β activation.


  • Organizational Affiliation

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Integrin alpha-V1,018Homo sapiensMutation(s): 0 
Gene Names: ITGAVMSK8VNRAVTNR
UniProt & NIH Common Fund Data Resources
Find proteins for P06756 (Homo sapiens)
Explore P06756 
Go to UniProtKB:  P06756
PHAROS:  P06756
GTEx:  ENSG00000138448 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06756
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Integrin beta-8727Homo sapiensMutation(s): 0 
Gene Names: ITGB8
UniProt & NIH Common Fund Data Resources
Find proteins for P26012 (Homo sapiens)
Explore P26012 
Go to UniProtKB:  P26012
PHAROS:  P26012
GTEx:  ENSG00000105855 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP26012
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Transforming growth factor beta-1 proproteinC [auth D]363Sus scrofaMutation(s): 0 
Gene Names: TGFB1
UniProt
Find proteins for P07200 (Sus scrofa)
Explore P07200 
Go to UniProtKB:  P07200
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07200
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[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-glucopyranoseD [auth C]6N-Glycosylation
Glycosylation Resources
GlyTouCan:  G56014GC
GlyCosmos:  G56014GC
GlyGen:  G56014GC
Entity ID: 5
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
E, F, G, H
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
M [auth A],
P [auth B],
Q [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
K [auth A],
L [auth A],
N [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
O [auth B]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.30 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesU54HL119893
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesR01HL113032
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesR01HL134183
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesR01GM098672
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesS10OD020054
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesS10OD021741
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesP41CA196276

Revision History  (Full details and data files)

  • Version 1.0: 2020-02-05
    Type: Initial release
  • Version 1.1: 2020-02-19
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary