| Autor: |
Aksana Vasilyeva, Jill E. Clodfelter, Michael J. Gorczynski, Anthony R. Gerardi, S. Bruce King, Freddie Salsbury, Karin D. Scarpinato |
| Jazyk: |
angličtina |
| Rok vydání: |
2010 |
| Předmět: |
|
| Zdroj: |
Journal of Nucleic Acids, Vol 2010 (2010) |
| Druh dokumentu: |
article |
| ISSN: |
2090-021X |
| DOI: |
10.4061/2010/162018 |
| Popis: |
Mismatch repair proteins modulate the cytotoxicity of several chemotherapeutic agents. We have recently proposed a “death conformation” of the MutS homologous proteins that is distinguishable from their “repair conformation.” This conformation can be induced by a small molecule, reserpine, leading to DNA-independent cell death. We investigated the parameters for a small reserpine-like molecule that are required to interact with MSH2/MSH6 to induce MSH2/MSH6-dependent cytotoxic response. A multidisciplinary approach involving structural modeling, chemical synthesis, and cell biology analyzed reserpine analogs and modifications. We demonstrate that the parameters controlling the induction of MSH2/MSH6-dependent cytotoxicity for reserpine-analogous molecules reside in the specific requirements for methoxy groups, the size of the molecule, and the orientation of molecules within the protein-binding pocket. Reserpine analog rescinnamine showed improved MSH2-dependent cytotoxicity. These results have important implications for the identification of compounds that require functional MMR proteins to exhibit their full cytotoxicity, which will avoid resistance in MMR-deficient cells. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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