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Research in my lab is focused on the structure/function relationships of proteins that regulate cellular metabolisms. To play their physiological roles, cells are required to adapt to a dynamic physiological environment which includes blood glucose levels, hypoxia, nutrients, hormones, circadian rhythms, and exercises. Such an adaptation requires continuous monitoring of the environment and concomitant adjusting of the manners and rates of their metabolisms. Our goal is to understand how these environmental factors transfer their signal to these regulatory proteins and transform them to cause metabolic changes at a molecular level. Our approach mainly involves X-ray crystallographic analysis of the conformational changes induced by phosphorylation, ligand-binding, and interactions with other biological macromolecules such as DNA and proteins. Our research is expanded to chemical biology, including structure-based drug design. The target proteins are the human bifunctional PFKFB1-4, which are involved in tissue-specific regulation of Fru-2,6-P2 (the most potent signal for regulating the rates of glycolysis and gluconeogenesis), the hypoxia-dependent transcriptional regulators, the CRE–binding proteins, and the key allosteric enzymes of metabolic pathways, i.e., PFK and GK.
Lee, Y.H., Li, Y., K. Uyeda, and Hasemann, C. (2003). ‘Tissue-specific structural differentiation shown in the liver isoform of 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase’. J. Biol. Chem. 278: 523-30.
Lee, Y.H., Nadaraia, S., Gu, D, Becker D.F., and Tanner, J.J. (2003). ‘Structure of the proline dehydrogenase domain of the multifunctional PutA flavoprotein’. Nature-Structural Biology. 10:109-114.
Lee, Y.H., Tanner, J.J., Larson, J.J., and Henzl, M.T. (2004). ‘Crystal structure of a high affinity variant of Rat a-Parvalbumin’. Biochemistry 43: 10008-10017.
Tanner, JJ, Agah, S, Lee, Y.H., Henzl, M.T. (2005). ‘Crystal Structure of the D94S/G98E Variant of Rat alpha-Parvalbumin. An Explanation for the Reduced Divalent Ion Affinity’. Biochemistry 44:10966-76.
Kim S.-G., Manes, N.P., El-Maghrabi, M.R., and Lee, Y. H. (2006) ‘Crystal Structure of the Hypoxia-Inducible Form of 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase (PFKFB3): A Possible New Target for Cancer Therapy’ J. Biol. Chem. 281:2939-44.
Pattarkine, M., Lee, Y.H., Tanner, J.J., and Wall, J. (2006). ‘Desulfobrio desulfrican G20 tetraheme cytochrome structure at 1.5 Å and cytochrome interactions with metal complex’. J. Mol. Biol. 358(5):1314-27.
Kim, S.-G., Bhattacharyya, G., Grove A., and Lee, Y.H. (2006) ‘Crystal structure of Dps-1, a Functionally Distinct Dps Protein from Deinococcus radiodurans’. J. Mol. Biol. 361:105-114.
Kim, S.-G., El-Maghrabi, M.Raafat, and Lee, Y. H. (2006) ‘Catalytic Mechanism of 6-Phosphofructo-2-Kinase of PFKFB: Crystal Structures of PFKFB3 in Ternary Complexes and Kinetic Studies. Submitted.