Description
Experimental Technique/Method:X-RAY DIFFRACTION
Resolution:1.82
Classification:CYTOKINE
Release Date:2017-03-01
Deposition Date:2016-11-15
Revision Date:2017-03-08#2017-05-10
Molecular Weight:21206.58
Macromolecule Type:Protein
Residue Count:186
Atom Site Count:1462
DOI:10.2210/pdb5tx2/pdb
Abstract:
The transforming growth factor β isoforms, TGF-β1, -β2, and -β3, are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-β pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. Despite the known importance of TGF-βs in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-β monomer, lacking the heel helix, a structural motif essential for binding the TGF-β type I receptor (TβRI) but dispensable for binding the other receptor required for TGF-β signaling, the TGF-β type II receptor (TβRII), as an alternative therapeutic modality for blocking TGF-β signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-β monomers and bound TβRII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-β signaling with a
Resolution:1.82
Classification:CYTOKINE
Release Date:2017-03-01
Deposition Date:2016-11-15
Revision Date:2017-03-08#2017-05-10
Molecular Weight:21206.58
Macromolecule Type:Protein
Residue Count:186
Atom Site Count:1462
DOI:10.2210/pdb5tx2/pdb
Abstract:
The transforming growth factor β isoforms, TGF-β1, -β2, and -β3, are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-β pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. Despite the known importance of TGF-βs in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-β monomer, lacking the heel helix, a structural motif essential for binding the TGF-β type I receptor (TβRI) but dispensable for binding the other receptor required for TGF-β signaling, the TGF-β type II receptor (TβRII), as an alternative therapeutic modality for blocking TGF-β signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-β monomers and bound TβRII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-β signaling with a
| Date made available | 2017 |
|---|---|
| Publisher | RCSB-PDB |