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- Title
Structure-based derivation of peptide inhibitors to target TGF-β1 receptor for the suppression of hypertrophic scarring fibroblast activation.
- Authors
Hu, Huan; Yang, Songlin; Zheng, Jianghong; Mao, Guangyu
- Abstract
The intermolecular recognition and interaction between human transforming growth factor β-1 ( TGF-β1) and its cognate receptor Tβ RII have been implicated in the pathological condition of hypertrophic scarring ( HS). Here, we attempted to rationally derive peptide inhibitors from the complex interface of TGF-β1 with Tβ RII to disrupt such interaction for the suppression of fibroblast activation involved in HS. A synthetic strategy that integrated computational design and fluorescence-based assay was described to examine the structural basis and energetic property of TGF-β1-Tβ RII crystal structure, from which a small peptide segment in the complex binding site was stripped artificially. Molecular dynamics simulations revealed that the linear peptide possesses a large intrinsic disorder that would incur considerable entropy penalty upon binding to Tβ RII; the peptide segment was then extended and cyclized by introducing a disulfide bond across its terminal residues that were premutated to cysteine. Normal mode analysis indicated that, as expected, the peptide flexibility was largely reduced upon the cyclization, and thus, the entropy penalty was minimized substantially, consequently promoting the spontaneous binding of peptide to Tβ RII. Fluorescence polarization assay confirmed that all linear peptides are typical non-binders of Tβ RII ( Kd = ND), while the designed cyclic peptides exhibit moderate or high affinity with Kd at micromolar level.
- Subjects
TRANSFORMING growth factors; HYPERTROPHIC scars; FIBROBLASTS; CRYSTAL structure; MOLECULAR dynamics; RING formation (Chemistry)
- Publication
Chemical Biology & Drug Design, 2017, Vol 90, Issue 3, p345
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12954