Research
Faculty Members
Quantitative biophysical life science（Chemistry）
Ueda TakumiProfessor
Education
2000: B. Sc. (Pharmaceutical Sciences) The University of Tokyo, Japan
2005: Ph.D. (Pharmaceutical Sciences) The University of Tokyo, Japan
Professional Experience
2005-2006 Researcher, Japan Biological Informatics Consortium
2007-2019 Research Associate, Graduate School of Pharmaceutical Sciences, The University of Tokyo
2013-2017 (Additional post) Faculty-Presto, Japan Science and Technology Agency, Tokyo, Japan
2019-2024 Associate Professor, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Award
2022Progress Award, The Nuclear Magnetic Resonance Society of Japan
Research theme
Quantitative elucidation of the biofunction-related conformational dynamics of drug-target proteins
Drug-target proteins exert their biofunctions with continuously changing their conformations. In relation to this point, NMR methods provide quantitative spatiotemporal information on proteins under conformational equilibria, including the structure of each state, exchange rate, and population. We are proceeding with studies on the elucidation of function-related conformational equilibria of drug-target proteins, including G protein-coupled receptors (GPCRs). These studies promote our understanding of the biological events and drug development.
Development of mid-size molecules that regulate activities of drug-target proteins using NMR
Mid-size molecules, such as atypical peptides, are promising drug modality potentially capable of targeting intracellular protein-protein interactions, which are difficult targets for conventional small-size drugs and antibodies. We utilize NMR to clarify their conformational “chameleonicity”: flexibly changing their dynamic conformation to adapt their environments, including aqueous solution, hydrophobic membrane, and the complex with the receptor, which determines their membrane permeability and affinity for the receptor.
Clarification of overall biological events by integrating multi-level experimental information using NMR
We are exploring methods for constructing models of biological events by integrating multi-scale experimental data, including atom-level precise structural information of drug-target proteins (by X-ray crystallography and cryo-electron microscopy) and cell biological real-time observation, by utilizing quantitative information on the function-related conformational equilibria obtained from NMR and exchange Monte-Carlo method, which can realize the comprehensive and effective optimization of multiple parameters in the model. Our study, which can be referred to as “Quantitative structural life science”, will establish novel approach for understanding biological events and accelerating drug development.
Representative achievements
Hosono, Y., Uchida, S., Shinkai, M., Townsend, CE., Kelly, CN., Naylor, MR., Lee, HW., Kanamitsu, K., Ishii, M., Ueki, R., Ueda, T., Takeuchi, K., Sugita, M., Akiyama, Y., Lokey, SR., Morimoto, J., Sando, S., "Amide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides", Nat. Commun. 14: 1416 (2023)
Mizumura, T., Kondo, K., Kurita, M., Kofuku, Y., Natsume, M., Imai, S., Shiraishi, Y., Ueda, T., Shimada, I. Activation of adenosine A2A receptor by lipids from docosahexaenoic acid revealed by NMR. Sci. Adv. 6: eaay8544 (2020)
Imai, S., Yokomizo, T., Kofuku, Y., Shiraishi, Y., Ueda, T., Shimada, I. Structural equilibrium underlying ligand-dependent activation of β2-adrenoreceptor.Nat. Chem. Biol. 16: 430-439 (2020)
Minato, Y., Ueda, T., Machiyama, A., Iwai, H.,Shimada, I. Dynamic domain arrangement of CheA-CheY complex regulates bacterial thermotaxis, as revealed by NMR. Sci. Rep. 7: 16462 (2017)
Minato, Y., Suzuki, S., Hara, T., Kofuku, Y., Kasuya, G., Fujiwara, Y., Igarashi, S., Suzuki, E., Nureki, O., Hattori, M., Ueda, T., Shimada, I. Conductance of P2X4 purinergic receptor is determined by conformational equilibrium in the transmembrane region, Proc. Natl. Acad. Sci. U. S. A. 113: 4741-4746 (2016)
Okude, J., Ueda, T., Kofuku, Y., Sato, M., Nobuyama, N., Kondo, K., Shiraishi, Y., Mizumura, T., Onishi, K., Natsume, M., Maeda, M., Tsujishita, H., Kuranaga, T., Inoue, M., Shimada, I. Conformational equilibrium of -opioid receptor determines its efficacies and functional selectivities. Angew. Chem. Int. Ed. 54: 15771-15776 (2015)
Kofuku, Y., Ueda, T., Okude, J., Shiraishi, Y., Kondo, K., Mizumura, T., Suzuki, S., Shimada, I. Functional dynamics of deuterated 2 -adrenergic receptor in lipid bilayers revealed by NMR spectroscopy. Angew. Chem. Int. Ed. 53: 13376-13379 (2014)
Kofuku, Y., Ueda, T., Okude, J., Shiraishi, Y., Kondo, K., Maeda, M., Tsujishita, H., Shimada, I. Efficacy of the 2-adrenergic receptor is determined by conformational equilibrium in the transmembrane region. Nat. Commun. 3: 1045 (2012)
Ueda, T., Nomoto, N., Koga, M., Ogasa, H., Ogawa, Y., Matsumoto, M., Stampoulis, P., Sode, K., Terasawa, H., Shimada, I. Structural basis of efficient electron transport between photosynthetic membrane proteins and plastocyanin in spinach revealed using nuclear magnetic resonance. Plant Cell 24, 4173-4186 (2012)
4.Yoshiura, C., Kofuku, Y., Ueda, T., Mase, Y., Yokogawa, M., Osawa, M., Terashima, Y., Matsushima, K., Shimada, I. NMR analyses of the interaction between CCR5 and its ligand using functional reconstitution of CCR5 in lipid bilayers. J. Am. Chem. Soc. 132: 6768-6777 (2010)
