Rational derivation, extension, and cyclization of self-inhibitory peptides to target TGF-β/BMP signaling in ONFH
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- 作者：Zhenhong Zhu ; Chi Zhang ; Wenqi Song
- 关键词：Transforming growth factor β ; 1 ; Self ; inhibitory peptide ; Rational molecular design ; Osteonecrosis of the femoral head
- 刊名：Amino Acids
- 出版年：2017
- 出版时间：February 2017
- 年：2017
- 卷：49
- 期：2
- 页码：283-290
- 全文大小：
- 刊物类别：Biomedical and Life Sciences
- 刊物主题：Biochemistry, general; Analytical Chemistry; Biochemical Engineering; Life Sciences, general; Proteomics; Neurobiology;
- 出版者：Springer Vienna
- ISSN：1438-2199
- 卷排序：49
文摘
The human transforming growth factor β (TGF-β)/bone morphogenic protein (BMP) signaling has been recognized as an attractive target to suppress fibroblast activation in osteonecrosis of the femoral head (ONFH). Here, we reported successful derivation of a self-inhibitory peptide from the crystal complex interface of TGF-β with its cognate receptor TβRI using rational molecular design and in vitro binding assay. Computational modeling suggested that the peptide possesses a large flexibility and would incur considerable entropy penalty. To minimize the entropy effect, the peptide was extended and cyclized to obtain a modified version of cyclic peptide. Molecular dynamics (MD) simulations revealed that the cyclic peptide exhibits larger rigidity and lower thermal motion in unbound state as compared to its linear counterpart, thus causing less entropy penalty upon binding to TGF-β. The computational findings were then substantiated by fluorescence polarization (FP) assays, that is, no binding affinity was detected for linear peptide (Kd = n.d.), while cyclic version was determined to have a moderate affinity (Kd = 76 ± 18 μM). Structural and energetic analysis identified two anchor residues Phe60 and Ser65 in cyclic peptide that can form a π–π stacking and a hydrogen bonding with the residues Trp30 and His68 of TGF-β, respectively, conferring high stability and specificity to the complex system.