探討人類端粒四股結構的結構轉換機制

王咨富

doi:10.6342/NTU.2013.02623

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探討人類端粒四股結構的結構轉換機制

Elucidation of the Mechanism of Structure Conversion in Human Telomeric G-quadruplexes

王咨富 , Ph.D　　Advisor：張大釗　　

繁體中文 DOI： 10.6342/NTU.2013.02623

人類端粒四股結構；結構轉換；離子效應；四股結構嵌合劑；去水合效應； Human telomere G-quadruplex ； Struture conversion ； Ion effect ； G-quadruplex ligand ； Dehydration effect

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Human telomere G-quadruplexes (G4) is a promising target for cancer therapy by telomerase inhibition. Thus, designing and synthesizing of a small molecule that can bind to G4 and inhibit telomerase has been a popular research topic. However, G-quadruplex has a variety of structures and it is not known which of these structures are likely to be present in living cells. Therefore, a rational design of selective ligands to G4 is challenging. Here, we synthesized a novel ligand and apply the technique of ITC, DSC, and NMR with site-specific isotope (15N) labeling to discuss the diversity of G4 structure and to find out the mechanism of structure conversion. The first part of my thesis discusses the mechanism of structure conversion of Human telomere G-quadruplex by sodium- potassium exchange. By solving the structure of Human telomere G-quadrupelx (HT23) under sodium form, we find the structure is the same as the potassium form. Instead of involving large conformation change, the process is mainly through the ion sequential exchange. The second part is applying the idea of solvent effect of PEG (polyethylene glycol) to ligand design where we optimized the fluorescence probe of 3,6-Bis(1-methyl-4-vinylpyridium) carbazole diiodide (BMVC) molecule by substituting a tetraethylene glycol in the N-9 position with a methyl-piperidinium cation to produce a new G4 stabilizer called BMVC-8C3O. The design principle based on solvent effect of PEG can induce structural change from non-parallel to parallel G4 and further stabilize the G4 structure for Human telomere G4 sequences. This provided a basis for the design of novel G4 ligands. The results show the modification of G4 ligand with the oxygen atom plays a crucial role for inducing parallel G4s, and provide evidence of the local dehydration effect from PEG where the local water structure is the key for induce conformational change of human telomere. The final part is applying the ligand to study the G4 strucutre conversion from hybrid to parallel. By NMR result, we discover the intermediate state and provide the kinetic pathway of structure conversion. The mechanism of G4 structure conversion can be further apply to the G4 biological function and G4 ligand design.

Reference ( 107 ) 〈TOP〉

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