TITLE：Chemical and Structural Biology of Selenium Nucleic Acids in Enzyme Catalysis (硒核酸的化学生物学与结构生物学)
SPEAKER：Zhen Huang (黄震), University Distinguished Professor Awardee, Georgia State University
TIME：Wednesday, November 19, 8:30-10:00
ROOM：beat365化学A楼5楼演讲厅
INVITER：颜德岳教授，朱新远教授

ABSTRACT:  Nucleic acids play multiple and essential functions in cells and expand dramatically the complexity of life by serving as genetic information carrier, catalyst, and regulator. Nucleic acid therapeutics exploration help better understand properties and behaviors of nucleic acids in vitro and in vivo. Nucleic acid chemical functionalization and structural study help understanding nucleic acids in cells and offer a great opportunity to therapeutic discovery. 3D structure studies of nucleic acids and their protein complexes provide novel insights into these bio-macromolecules, potential drug targets. Crystallography is a powerful tool for structure determination of nucleic acids and protein-nucleic acid complexes with high resolution. However, crystallization and phase determination, two major bottle-neck problems, have largely slowed down structural determination of nucleic acids and their protein complexes. Crystal structures of protein-nucleic acid complexes are commonly determined by selenium-derivatized proteins via MAD or SAD phasing. We report the first protein-nucleic acid complex structure determined by selenium-derivatized nucleic acids. The RNase H/RNA/DNA complex is used as an example to demonstrate the proof of principle. Our high-resolution crystal structure indicates that this Se-replacement results in a local subtle unwinding on RNA/DNA substrate duplex, thereby shifting the RNA scissile phosphate closer to the transition state of the enzyme-catalyzed reaction. We also observed that the scissile phosphate forms a hydrogen bond with the water nucleophile and helps positioning the water molecule in the structure. Consistently, we have discovered that the substitution of a single oxygen atom with a selenium atom on a DNA-guiding sequence can largely accelerate RNase H catalysis. Our structural and catalytic studies shed new light on the guide-dependent RNA cleavage and discovery of novel oligonucleotide therapeutics. Furthermore, our laboratory has pioneered and developed atom-specific substitution of nucleic acid oxygen with selenium that can be used as an atomic probe for structure and function studies of nucleic acids. This work is supported by NIH (R01GM095881 and GM095086) and NSF (MCB-0824837 and CHE-0750235).

Biography:  Zhen Huang was born in 1964 and raised in Sichuan, China. He received his B.S. degree from Sichuan University in 1984 (under the supervision of Professor Shulin Chen), M.S. from Peking University in 1987 (under the supervision of Professor Wen Zhong), and Ph.D. degree from Swiss Federal Institute of Technology (ETH, Zurich) in 1994 (under the supervision of Professor Steven Benner). In 1994, he joined the Department of Genetics at Harvard Medical School as a research fellow, in Laboratory of Professor Jack Szostak (Nobel Laureate in Medicine in 2009). He was hired in 1998 by Brooklyn College, City University of New York, as assistant professor and was later promoted to associate professor with tenure. Dr. Huang was recruited in 2004 to Chemistry Department, Georgia State University, is Professor of Chemistry and Chemical and Structural Biology, and is also University Distinguished Professor Awardee of Georgia State University. He has received several awards, including Georgia Distinguished Cancer Scientists Award, from The State of Georgia (GCC), and University Distinguished Professor Award. He is also very active in community services: he has served as editors and guest editors for several journals and books, and is the first President of Chinese-American Chemistry & Chemical Biology Professors Association (CAPA; also one of the three Co-Founders). He has pioneered and developed selenium and tellurium derivatizations of nucleic acids for structure and function studies of nucleic acids, protein-nucleic acid complexes, and nucleic acid-small molecular ligands (such as anticancer drugs). His current research interests are in selenium and tellurium derivatizations of DNAs and RNAs for X-ray crystallographic studies of nucleic acids and protein complexes (especially for Cancer Research), synthesis of analogs of nucleosides and nucleotides for structure, function and anticancer studies, development of RNA microchip technology for direct detection and quantitation of gene expression profile for Cancer Early Detection, nanomaterial-assisted novel RNA microchip, modified nucleic acid-based nano-medicine, nucleic acid-based cancer diagnosis, in vitro selection, evolution and characterization of ligand-binding and catalytic RNAs and DNAs. His research has been funded by federal agencies, including NIH, NSF, DOD, and CDC, state funding agencies, the distinguished cancer scholar award, and private fundings (such as industries). He has received several US and European patents, and many US and international patents are pending.