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- Title
Structure‐based discovery and redesign of TGF‐β1 Elbow epitope recognition by its type‐II receptor in hypertrophic scarring biotherapy.
- Authors
Chen, Xiaoting; Wang, Huixiong; Yang, Songlin; Zheng, Jianghong; Liu, Xiangdong; Mao, Guangyu
- Abstract
Transforming growth factor‐β1 (TGF‐β1) signaling pathway has been implicated in the fibroblast activation of hypertrophic scarring (HS). Previously, we proposed a new biotherapeutic strategy to combat HS by disrupting the intermolecular interaction of TGF‐β1 with its cognate type‐II receptor (TβR‐II). Here, we further demonstrate that the binding site of TGF‐β1 to TβR‐II is not overlapped with the conformational wrist epitope and linear knuckle epitope that are traditionally recognized as the functional binding sites of bone morphogenetic protein‐2 (BMP‐2) to its type‐II receptor (BMPR‐II), which can thus be regarded as a new functional site we called elbow epitope. Structural, energetic, and dynamic investigations reveal that the elbow epitope consists of two sequentially discontinuous, spatially vicinal segments Loop30‐34 and Turn90‐95; they cannot work effectively to independently interact with TβR‐II. Rational redesign of the epitope is performed using an integrated in silio‐in vitro method based on crystal and modeled structure data. In the procedure, the two epitope segments are split from the interface of TGF‐β1‐TβR‐II complex and then connected with each other in a head‐to‐tail manner by adding a flexible poly‐(Gly)n linker between them, thus resulting in a series of combined peptides. We found that the peptide affinity reaches maximum at n = 2, which shares a consistent binding mode with the elbow epitope at native complex interface. The linker of either too long (n > 2) or too short (n < 2) cannot properly place the gap space between the two segments, thus impairing the binding compatibility of designed peptides with TβR‐II active site.
- Subjects
HYPERTROPHIC scars; ELBOW; BIOTHERAPY; BINDING sites; MOLECULAR recognition
- Publication
Journal of Molecular Recognition, 2021, Vol 34, Issue 4, p1
- ISSN
0952-3499
- Publication type
Article
- DOI
10.1002/jmr.2881