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Title: Structural studies on a p53-MDM2 inhibitor
Author: Duncan, S. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2002
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The 53 kDa phosphoprotein, p53 plays a critical role in the regulation of cell proliferation and development of genetic abnormalities by inducing G1 arrest or apoptosis in response to DNA damage. It also forms a stable complex with the MDM2 protein, in which state, the transactivation domain of p53 is concealed from the transcriptional machinery and is unable to induce G1 arrest or apoptosis. p53 activates the transcription of the mdm2 gene, so the levels of MDM2 and the activity of p53 are kept under the control of an autoregulatory feedback loop. When overexpressed, MDM2 acquires tumorigenic potential. It is possible that tumours expressing abnormally high levels of MDM2 could be treated with small molecules that disrupt the p53-MDM2 interaction, thereby restoring normal function to wild-type p53. A peptidic secondary metabolite from Microdochium caespitosum has been identified as an inhibitor of the p53-MDM2 interaction. The primary structure of this natural product, chlorofusin, has been determined by NMR, mass spectrometry and chiral GC-MS. The three-dimensional structure has been calculated with random simulated annealing, based on NOE and coupling restraints. An investigation into the biosynthetic origin of the chromophore of chlorofusin was then carried out with 13C-labelled sodium acetate feeding experiments. Finally, the N-terminal regions of both MDM2 and p53 were expressed for SPR binding assays with chlorofusin, to further investigate chlorofusin's mode of action. It was shown that chlorofusin binds to the N-terminal region of MDM2. As an antagonist of the p53-MDM2 interaction, chlorofusin could be useful in the design of new drug candidates for the treatment of tumours arising from the overexpression of MDM2.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available