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Study on the Mechanism of Interaction between Dipeptidyl Peptidase 4 and Inhibitory Peptides Based on Gaussian Accelerated Molecular Dynamic Simulation.
Liu, Yuyang; Zhao, Wencheng; Jiang, Yongxin; Xing, Shu; Li, Wannan.
Afiliação
  • Liu Y; Edmond H. Fischer Signal Transduction Laboratory, School of Life Sciences, Jilin University, Changchun 130012, China.
  • Zhao W; Edmond H. Fischer Signal Transduction Laboratory, School of Life Sciences, Jilin University, Changchun 130012, China.
  • Jiang Y; Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China.
  • Xing S; Edmond H. Fischer Signal Transduction Laboratory, School of Life Sciences, Jilin University, Changchun 130012, China.
  • Li W; Edmond H. Fischer Signal Transduction Laboratory, School of Life Sciences, Jilin University, Changchun 130012, China.
Int J Mol Sci ; 25(2)2024 Jan 10.
Article em En | MEDLINE | ID: mdl-38255913
ABSTRACT
Dipeptidyl peptidase 4 (DPP4) inhibitors can effectively inhibit the activity of DPP4, increasing the concentrations of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which allows for them to effectively contribute to the reduction of blood sugar levels. Leu-Pro-Ala-Val-Thr-Ile-Arg (LPAVTIR) and Leu-Pro-Pro-Glu-His-Asp-Trp-Arg (LPPEHDWR) were the two peptides with the strongest inhibitory activity against DPP4 selected from silkworm pupa proteins. In this study, four systems were established Apo (ligand-free DPP4), IPI (IPI-bound DPP4), LPAVTIR (LPAVTIR-bound DPP4), LPPEHDWR (LPPEHDWR-bound DPP4), and Gaussian accelerated molecular dynamic (GaMD) simulation was conducted to investigate the mechanism of action of two inhibitory peptides binding to DPP4. Our study revealed that the LPAVTIR peptide possessed a more stable structure and exhibited a tighter binding to the Ser630 active site in DPP4, thus exhibiting a favorable competitive inhibition effect. In contrast, the LPPEHDWR peptide caused the horizontal α-helix (residues 201-215) composed of Glu205 and Glu206 residues in DPP4 to disappear. The spatial arrangement of active sites Ser630 relative to Glu205 and Glu206 was disrupted, resulting in enzyme inactivation. Moreover, the size of the substrate channel and cavity volume was significantly reduced after the binding of the inhibitory peptide to the protein, which was an important factor in the inhibition of the enzyme activity. A similar effect was also found from IPI (our positive control). By stabilizing the active site of DPP4, the IPI peptide induced the disappearance of the horizontal α-helix and a notable reduction in the active cavity volume. In conclusion, our study provided a solid theoretical foundation for the inhibitory mechanisms of IPI, LPAVTIR, and LPPEHDWR on DPP4, offering valuable insights for advancing the development of drug targets for type 2 diabetes.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Diabetes Mellitus Tipo 2 / Inibidores da Dipeptidil Peptidase IV Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Diabetes Mellitus Tipo 2 / Inibidores da Dipeptidil Peptidase IV Idioma: En Ano de publicação: 2024 Tipo de documento: Article