Synthesis, Structure, Function and Biomedical Studies of Nucleic Acid Derivatized with Selenium
نویسندگان
چکیده
Nucleic acids are macromolecules in cells for storing and transferring genetic information. Moreover, nucleic acids, especially RNAs, can fold into well-defined 3D structures and catalyze biochemical reactions. As ubiquitous biological molecules in all living systems, nucleic acids are important drug targets, and they can also be used in diagnostics and therapeutics. Structural information of nucleic acids provides the foundation for DNA and RNA function studies. X-ray crystallography has been a useful tool for structural studies of bio-macromolecules at atomic level. There are two major problems in macromolecular crystal structure determination: phasing and crystallization. Although selenium derivatization is routinely used for solving novel protein structures through the MAD phasing technique, the phase problem is still a critical issue in nucleic acid crystallography. The covalent seleniumderivatization of nucleic acids has been proven to be a useful strategy for solving the phase problem in nucleic acid X-ray crystallography. Besides the facilitation of nucleic acid crystallography, there is also a wide range of other applications for selenium-derivatized nucleic acids (SeNA). The investigation presented in this dissertation mainly focuses on the following research subjects (1) Synthesis and characterization of selenium-derivatized nucleic acids for X-ray crystallography, especially phosphoroselenoate RNAs. They are generated and used for crystallization. (2) Application of selenium-derivatized RNA for RNA interference. Phosphoroselenoate RNAs are tested for RNAi activities. (3) Synthesis and characterization of the uridine 5’-triphosphate modified with selenium at position 4. (4) Facile synthesis and antitumor activities of selenium modified deoxyribonucleosides. MeSe-thymidine nucleosides have shown antitumor activity in cell assays. . . INDEX WORDS: Selenium, Nucleic acids, RNA, DNA, PSe-RNA, X-ray crystallography, Anti-cancer drug, siRNA, RNA interference, SYNTHESIS, STRUCTURE, FUNCTION AND BIOMEDICAL STUDIES OF NUCLEIC ACID DERIVATIZED WITH SELENIUM
منابع مشابه
Synthesis, Structure and Function Studies of Selenium and Tellurium Derivatized Nucleic Acids
Nucleic acids play important roles in living systems by storing and transferring genetic information and directing protein synthesis. Recently, it was found that nucleic acids can catalyze chemical and biochemical reactions similar to protein enzymes. In addition, they can also serve as drug targets for the treatment of deadly diseases such as AIDS and cancers. As a result, the 3D structure stu...
متن کاملStructure and Function Studies of Selenium Substituted Nucleic Acids
Nucleic acids are responsible for the storage of genetic information and directly participate in gene replication, transcription and expression, and thereby the control of nucleic acids leads to the regulation of genetic information flow and gene expression. Meanwhile, many non-coding RNAs are involved in signal transduction directly. Moreover, nucleic acid-based therapeutic strategies have bee...
متن کاملSelenium derivatization of nucleic acids for crystallography
The high-resolution structure of the DNA (5'-GTGTACA-C-3') with the selenium derivatization at the 2'-position of T2 was determined via MAD and SAD phasing. The selenium-derivatized structure (1.28 A resolution) with the 2'-Se modification in the minor groove is isomorphorous to the native structure (2.0 A). To directly compare with the conventional bromine derivatization, we incorporated bromi...
متن کاملNovel complex MAD phasing and RNase H structural insights using selenium oligonucleotides.
The crystal structures of protein-nucleic acid complexes are commonly determined using selenium-derivatized proteins via MAD or SAD phasing. Here, the first protein-nucleic acid complex structure determined using selenium-derivatized nucleic acids is reported. The RNase H-RNA/DNA complex is used as an example to demonstrate the proof of principle. The high-resolution crystal structure indicates...
متن کاملSynthesis of selenium-derivatized nucleosides and oligonucleotides for X-ray crystallography.
We report here the synthesis of nucleoside and oligonucleotide analogs containing selenium, which serves as an anomalous scattering center to enable MAD phase determination in nucleotide X-ray crystallography. We have developed a phase transfer approach to introduce the selenium functionality in A, C, G, T, and U nucleosides at 5'-positions. In the incorporation of the selenium functionality, t...
متن کامل