Pharmacology and Toxicology - Research

Y. Whitney Yin, M.D., Ph.D.

Assistant Professor

Research Interests

Our research focuses on several aspects of DNA replication and gene transciption using methods of crystallography and other biochemistry and biophysics.
Structural basis for anti-HIV drug toxicity
Human mitochondrial DNA polymerase has been implicated in drug toxicity of antiviral drugs designed against HIV reverse transcriptase. We use structures of human mitochondrial DNA polymerase as a guide for designing more potent and less toxic antiviral agents.
Mechanism for gene expression in mitochondria
Gene expression system in mitochondria shows a clear viral origin: The mitochondrial RNA polymerase active site domain resembles that of T7 bacteriophage. however, mitoRNA polymerase differs from T7 RNA polymerase by functionallly depending on transcription factors. Studies of mitochondrial transcription not only provides us important links between human diseases and gene expression defects, but also a valuable point on evolution of transcription systems.
Bioengineering of T7 RNA polymerase for new functions
T7 RNA polymerase is a major tool for RNA synthesis in vitro. We are working on reengineering the polymerase to gain various functions for generation modified RNA.

Selected Publications

Lee, Y.S., Molineux I.J, Yin, Y.W, A single mutation in human mitochondrial DNA polymerase pol gammaA affects both polymerization and proofreading activities, but only as a holoenzyme, J Biol Chem, 2010 May 30.

Lee, YS, Lee, SJ, Demeler, D, Molineux, IJ, Johnson, KA, Yin, YW, Each monomer of the dimeric accessory protein for human mitochondrial DNA polymerase has a distinct role in conferring processivity, J Biol Chem, 2010 8;285(2):1490-9.

Lee, YS, Kennedy, WD, Yin, YW,Structural insights into human mitochondrial DNA replication and disease-related polymerase mutations. Cell, 2009, 139(2):312-24.

Commentary. Cell. 2009 Oct 16; 139(2):231-3.

Kennedy, PW, Momand RJ, and Yin, YW, Mechanism for de novo RNA synthesis and initiating nucleotide specificity by T7 RNA polymerase. J Mol Biol. 2007 370(2):256-68.

Challa, M, Malladi, S, Pellock, BJ, Dresnek, D, Varadarajan, S, Yin, YW White, K, Bratton, SB. Drosophila Omi, a mitochondrial-localized IAP antagonist and proapoptotic serine protease. 2007 EMBO J 26(13):3144-56.

Yin, YW and Steitz, TA. Mechanism for T7 RNA polymerase translocation and helicase activity. 2004 Cell, 116(3):393-404.

Rataileau, P, Huang, X, Yin, YW, Vachette, P, Vonrhein, C, Bricogne, G, Roversi, P, Ilyin, V, Carter, CW Jr, 2.2 A crystal structure of typtophanyl-tRNA synthetase complexed with ATP in a closed, pre-transition-state conformation. 2003 J Mol Biol. 325(1):39-63.

Yin,YW and Steitz, TA: Structural basis for the transition from initiation to elongation transcription in T7 RNA polymerase. 2002 Science, 298(5597):1387-95.

Carter, CW Jr, Ilyin V, Yin Y, Huang X and Retailleau P: The TrpRS Conformations Stabilize a Dynamic, Dissociative Transition State in Using Crystallography to Understand Enzyme Mechanisms. Transactions of the American Crystallographic Association, Inc 35:19-36, 2001.

Rateileau, P, Yin Y,, Hu M, Roach J, Bricogne G, Vonrhein C, Roversi P, Blanc E, Sweet RM, Carter CW Jr. High-resolution experimental phases for tryptophanyl-tRNA synthetase (TrpRS) complexed with tryptophanyl-5'AMP. 2001 Acta Crystallogr D57:1595-608.

Ilyin, V., Li, G., Temple, B., Yin, Y., Carter, C.W., Jr. 2.9A crystal structure of ligand-free Tryptophanyl tRNA synthetase Domain Movements Fragment the Adenine Nucleotide Binding Site". 2000 Protein Science 9-218-231.

Yin, Y. and Carter, C.W. Incomplete Factorial Design and Response Surfaces Methods: Yield Optimization of tRNA from in vitoro T7 RNA Polymerast Transcription." 1996 Nucleic Acids Res. 24 1279-1286.

Carter, C.W. and Yin, Y. Quantitative Analysis in the Characterization and Optimization of Protein Crystal Growth. 1994, Acta. Cryst. D50, 572-590.