03.02
Facilitation of Nucleic Acid Crystallization and
Phasing by Selenium-Nucleic Acids
Zhen Huang1, Wen Zhang1, Sibo Zhang1, Huiyan Sun1, Julianne Caton-Williams1
1
Georgia State University
Our laboratory has pioneered and developed atom-specific substitution of nucleic acid
oxygen with selenium, which can be used as an atomic probe for structure and function
studies of nucleic acids. As oxygen and selenium are in the same elemental family, the
atom-specific replacement by replacing nucleotide oxygen with selenium has revealed
novel chemistry, structure, function and mechanism of nucleic acids. The Se derivatization
leads to a novel paradigm of nucleic acids and facilitates drug discovery. Moreover, X-ray
crystallography is a powerful tool for structure determination of DNA and RNA structures,
RNA-protein and DNA-protein complexes with high resolution. However, crystallization and
phase determination are the two bottleneck problems and have largely slowed down
structural determination of nucleic acids and their protein complexes with novel structures
and folds. Our selenium nucleic acid strategy has demonstrated great potentials as a
general methodology for structure and function studies of nucleic acids as well as their
protein complexes. Furthermore, we find that the Se-derivatized nucleic acids have
virtually identical structures to the corresponding natives, while the conventional
Br-derivatization caused severe perturbations on the local backbone and hydration. We
have also found that the Se-derivatization can significantly facilitate crystallization and the
diffraction quality is high. Our results suggest that the Se derivatization is a better
alternative to the conventional Br derivatization. This Se derivatization strategy via the
atom-specific substitution will significantly facilitate crystal structure studies of nucleic
acids as well as their protein complexes. Excitingly, we have recently determined the first
nucleic acid-protein complex via the nucleic acid Se-derivatization and the MAD phasing.
This work is supported by NIH (R01GM095881 and GM095086) and NSF (MCB-0824837
and CHE-0750235).
Selected Publications:
1. Huiyan Sun, Jia Sheng, Abdalla E. A. Hassan, Sibo Jiang, Jianhua Gan and Zhen Huang*,
“Novel RNA Base Pair with Higher Specificity using Single Selenium Atom”, Nucleic Acids
Res., 2012, 40, 5171-5179.
2. Jia Sheng, Wen Zhang, Abdalla E. A. Hassan, Jianhua Gan, Alexei Soares, Song Geng, Yi
Ren, Zhen Huang*, "Hydrogen Bond Formation between the Naturally Modified Nucleobase
and Phosphate Backbone", Nucleic Acids Research, 2012, 40, 8111-8118.
3. Wen Zhang, Jia Sheng, Abdalla E. Hassan, and Zhen Huang*, "Synthesis of Novel
2’-Deoxy-5-(Methylselenyl)Cytidine and Se-DNAs for Structure and Function Studies",
Chemistry-An Asian Journal, 2012, 7, 476-479.
4. Lin, L.; Sheng, J.; Huang, Z. Chemical Society Reviews, 2011, 40, 4591.
5. Sheng, J.; Hassan, A. E. A.; Zhang, W.; Zhou, J.; Xu, B.; Soares, A. S.; Huang, Z. Nucleic
Acids Res., 2011, 39, 3962.
6. Caton-Williams, J.; Lin, L.; Smith, M.; Huang, Z. Chemical Communications, 2011, 47,
8142.
7. Abdalla E. A. Hassan, Jia Sheng, Wen Zhang, and Zhen Huang*, "High Fidelity of Base
Paring by 2-Selenothymidine in DNA", Journal of American Chemical Society, 2010, 132,
2120-2121.
8. Jozef Salon, Jia Sheng, Jianhua Gan, Zhen Huang*, "Synthesis and crystal structure of
2’-Se-modified guanosine containing DNA", J. Org. Chem., 2010, 75, 637-641.
9. Jia Sheng, Abdalla Hassan, Zhen Huang*, "Synthesis of the First Tellurium-Derivatized
Oligonucleotides for Structural and Functional Studies", Chemistry - A European Journal,
2009, 15, 10210-10216.
10. Julianne Caton-Williams, Zhen Huang*, "Synthesis and DNA Polymerase Incorporation
of Colored 4-Selenothymidine Triphosphate with a Single Atom Substitution", Angewandte
Chemie Int. Ed., 2008, 47, 1723-1725.
11. Jozef Salon, Jiansheng Jiang, Jia Sheng, Oksana O. Gerlits, Zhen Huang*, "Derivatization
of DNAs with Selenium at 6-Position of Guanine for Function and Crystal Structure
Studies", Nucleic Acids Research, 2008, 36, 7009-7018.
12. Jiang, Sheng, Carrasco, Huang*, “Selenium Derivatization of Nucleic Acids for
Crystallography”, Nucleic Acids Research, 2007, 35, 477-485.
13. Salon, Sheng, Jiang, Chen, Caton-Williams, Huang*, “Oxygen Replacement with
Selenium at the Thymidine 4-position for the Se-Base-Paring and Crystal Structure
Studies”, Journal of American Chemical Society, 2007, 129, 4862-4863.