5TX4

Derivative of mouse TGF-beta2, with a deletion of residues 52-71 and K25R, R26K, L51R, A74K, C77S, L89V, I92V, K94R T95K, I98V single amino acid substitutions, bound to human TGF-beta type II receptor ectodomain residues 15-130

Summary for 5TX4

• Entry DOI: 10.2210/pdb5tx4/pdb
• Related: 5TX2 5TX6
• Descriptor: TGF-beta receptor type-2, Transforming growth factor beta-2 (3 entities in total)
• Functional Keywords: tgf-beta, tgf-beta type ii receptor, transferase-cytokine complex, transferase/cytokine
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 23726.23

Authors

Hinck, A.P.,Kim, S. (deposition date: 2016-11-15, release date: 2017-03-01, Last modification date: 2024-10-23)

Primary citation

Kim, S.K.,Barron, L.,Hinck, C.S.,Petrunak, E.M.,Cano, K.E.,Thangirala, A.,Iskra, B.,Brothers, M.,Vonberg, M.,Leal, B.,Richter, B.,Kodali, R.,Taylor, A.B.,Du, S.,Barnes, C.O.,Sulea, T.,Calero, G.,Hart, P.J.,Hart, M.J.,Demeler, B.,Hinck, A.P.
An engineered transforming growth factor beta (TGF-beta ) monomer that functions as a dominant negative to block TGF-beta signaling.
J. Biol. Chem., 292:7173-7188, 2017

PubMed 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 of 20-70 nm Investigation of the mechanism showed that the high affinity of the engineered monomer for TβRII, coupled with its reduced ability to non-covalently dimerize and its inability to bind and recruit TβRI, enabled it to bind endogenous TβRII but prevented it from binding and recruiting TβRI to form a signaling complex. Such engineered monomers provide a new avenue to probe and manipulate TGF-β signaling and may inform similar modifications of other TGF-β family members.

PubMed: 28228478
DOI: 10.1074/jbc.M116.768754

Experimental method

X-RAY DIFFRACTION (1.876 Å)