Molecular Dynamics Simulations on the Binding Modes of GSK3β-GSKIP and Keap1-Nrf2
| Autor: | Cheng-Wei Lo, 羅振維 |
|---|---|
| Rok vydání: | 2010 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 98 Molecular dynamics (MD) simulations have long been recognized as a useful tool in providing atomic level details on interpretation of biomolecular experimental observations. In this study we applied MD simulations to investigate the protein-protein interaction of two systems, namely, GSK3β-GSKIP and Keap1-Nrf2, and compared our findings with experimental data from literatures. GSKIP is a newly discovered protein interacting with GSK3β, that participates in a number of signal transduction pathways related to the cancers. In the first part of this thesis, we determined the binding mode between GSK3β and a peptide derived from GSKIP. Based on the complex structure, we studied three mutant systems, including D264A, V267G, and Y288F, to explain the roles of these three amino acids on GSK3β in accommodating GSKIP, as pointed out earlier. Meanwhile, the determined GSK3β−GSKIP complex structure was compared with two other known complexes, GSK3β−AxinGID and GSK3β−FRATide, which are essential in WNT signal transduction pathway. Our results showed that all these three peptides share a common motif, L(A)-X-X-R-L, and reside in the same groove in GSK3β. Our modeling result suggests that GSK3β−GSKIP behaves similar to GSK3β−AxinGID. The second part of this thesis focuses on Keap1 and a peptide derived from Nrf2, a protein in response to the cellular oxidative stress. In the circumstance of no stress, Keap1 represses Nrf2. In clinical research it was demonstrated that their interaction is abolished by a number of single point mutations such as R415A and Y572A in Keap1, and T80A in Nrf2. Deleting the CTR domain in Keap1 also fails the complex formation. Herein, we studied the wild type and the above-mentioned mutants to provide unbinding mechanisms upon mutations. We also revealed the cause of unbinding due to the CTR deletion. Interestingly, we found that Nrf2’s T80 does not contribute greatly in associating with Keap1 but plays a pivotal role in maintaining the peptide in a perfect anti-parallel β strand conformation to fit in the Keap1 binding surface. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
| Externí odkaz: |
|