構造モダリティ研究チーム

研究詳細 ： 重点課題

担当：竹内　恒　　研究チーム長

研究テーマ

■ バイオ医薬品の立体構造的評価手法の確立
独自の15N観測技術を発展させ高分子バイオ医薬品に適用することで、最終製剤と同じ溶液条件で、立体構造の同一性や変性に伴う構造変化を評価する手法を確立する。

■ 中分子医薬の高機能化技術の確立
溶液NMR法を用いた独自の動的立体構造解析技術により、中分子の溶媒環境の変化や標的との相互作用に伴う立体構造転換を解析することで、中分子の論理的な高機能化を行う技術を確立する。

■ 動的構造に基づく創薬技術の確立
溶液NMR法を用いた独自の動的立体構造解析技術により、 薬剤と標的タンパク質が複合体を形成した際の運動性や立体構造の変化を、リード最適化に活用する技術を確立する。

研究成果、論文リスト等

2017

Dynamic equilibrium on DNA defines transcriptional regulation of a multidrug binding transcriptional repressor, LmrR. Sci Rep, in press, (2017). Takeuchi K, Imai M, Shimada I.

2016

Revisiting the Field Dependence of TROSY Sensitivity J Biomol NMR, 66, 221-225, (2016). Takeuchi K, Arthanari H, Wagner G.

Quantitative Structure-activity Relationship (QSAR) Models for Docking Score Correction. Mol Inf, 36, 1600013, (2016). Fukunishi Y, Yamasaki S, Yasumatsu I, Takeuchi K, Kurosawa T, Nakamura H.

Improvement of affinity and thermodynamic properties of weak-affinity ligands by NMR-based evaluation of local dynamics and surface complementarity in the bound state. Angew Chem Int Ed, 55, 14606-14609, (2016). *Mizukoshi Y, *Takeuchi K, Arutaki M, Tokunaga Y, Takizawa T, Hanzawa H, Shimada I, (*equal contribution).

Structural reverse genetics study of the PI5P4Kβ-nucleotide complexes reveals the presence of the GTP bioenergetic system in mammalian cells. FEBS J, 283, 3556–3562, (2016). Takeuchi K, Senda M, Lo YH, Kofuji S, Ikeda Y, Sasaki AT, Senda T.

Use of multiple cryoprotectants to improve diffraction quality from protein crystals. Cryst Growth Des,16, 1565–1571, (2016). Senda M, Hayashi T, Hatakeyama M, Takeuchi K, Sasaki AT, Senda T.

Nitrogen-detected TROSY yields comparable sensitivity to proton-detected TROSY for non-deuterated, large proteins under physiological salt conditions. J Biomol NMR, 64, 143-151, (2016). Takeuchi K, Arthanari H, Imai M, Wagner G, Shimada I.

The Lipid Kinase PI5P4Kβ Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis. Molecular Cell,61, 187–198, (2016). *Sumita K, *Lo TH, *Takeuchi K, Senda M, Kofuji S, Ikeda Y, Terakawa J, Sasaki M, Yoshino H, Majd N, Zheng Y, Kahoud ER, Yokota T, Emerling BM, Asara JM, Ishida T, Locasale JW, Daikoku T, Anastasiou D, Senda T, Sasaki AT. (*equal contribution).

2015

Nitrogen detected TROSY at high field yields high resolution and sensitivity for protein NMR. J Biomol NMR, 63323-331, (2015). Takeuchi K, Arthanari H, *Shimada I, *Wagner G.,

Structure-Based Development of a Protein-Protein Interaction Inhibitor Targeting Tumor Necrosis Factor Receptor-Associated Factor 6. J Med Chem, 58, 5674-5683, (2015). Moriya J, Takeuchi K, Tai K, Arai K, Kobayashi N, Yoneda N, Fukunishi Y, Inoue A, Kihara M, Murakami T, Chiba K, Shimada I.

Increased resolution of aromatic cross peaks using alternate 13C labeling and TROSY, J Biomol NMR, 62, 291-301, (2015). Milbradt AG, Arthanari H, Takeuchi K, Boeszoermenyi A, Hagn F, Wagner G.

Development of a method for reconstruction of crowded NMR spectra from undersampled time-domain data. J Biomol NMR, 62,31-41, (2015). Ueda T, Yoshiura C, Matsumoto M, Kofuku Y, Okude J, Kondo K, Shiraishi Y, Takeuchi K, Shimada I.

Suppression of problematic compound oligomerization by cosolubilization of nondetergent sulfobetaines. ChemMedChem, 10,736-741, (2015). Mizukoshi Y, Takeuchi K, Arutaki M, Takizawa T, Hanzawa H, Takahashi H, Shimada I.

2014

Dynamic multidrug recognition by multidrug transcriptional repressor LmrR. Sci Rep, 4,6922, (2014). Takeuchi K, Tokunaga Y, Imai M, Takahashi H, Shimada I.

NMR resonance assignments of the catalytic domain of human serine/threonine phosphatase calcineurin in unligated and PVIVIT-peptide-bound states. Biomol NMR Assign, 9, 201-205, (2015). Takeuchi K, Sun ZY, Li S, Gal M, Wagner G.

Allosteric enhancement of MAP kinase p38α's activity and substrate selectivity by docking interactions. Nat Struct Mol Biol, 21,704-711, (2014). Tokunaga Y, Takeuchi K, Takahashi H, Shimada I.

The LxVP and PxIxIT NFAT motifs bind jointly to overlapping epitopes on Calcineurin's catalytic domain distant to the regulatory domain. Structure, 22,1016-1027, (2014). Gal M, Li S, Luna RE, Takeuchi K, Wagner G.

Cross-saturation and transferred cross-saturation experiments. Quart Rev Biophy, 47,143–187, (2014). Ueda T, Takeuchi K, Nishida N, Stampoulis P, Kofuku Y, Osawa M, Shimada I.

Structure-based approach to improve a small-molecule inhibitor by the use of a competitive Peptide ligand. Angew Chem Int Ed, 53,2597-601, (2014). Ono K, Takeuchi K, Ueda H, Morita Y, Tanimura R, Shimada I, Takahashi H.

Functional dynamics of cell surface membrane proteins. J Magn Reson, 241, 86-96, (2014). Nishida N, Osawa M, Takeuchi K, Imai S, Stampoulis P, Kofuku Y, Ueda T, Shimada I.

[Functional dynamics of protein complex by NMR], NMR (J Soc NMR), 5,83-89, (2014) Takeuchi K, Shimada I.

2013

Degradation of Activated K-Ras Orthologue via K-Ras Specific Lysine Residues is Required for Cytokinesis. J Biol Chem, 289. 3950-3959, (2013). Sumita K, Yoshino H, Sasaki M, Majd N, Kahoud ER, Takahashi H, Takeuchi K, Kuroda T, Lee S, Charest PG, Takeda K, Asara JM, Firtel RA, Anastasiou D, Sasaki AT.

Rapid identification of ligand-binding sites by using an assignment-free NMR approach. J Med Chem, 56,9342-9350, (2013). Kodama Y, Takeuchi K, Shimba N, Ishikawa K, Suzuki E, Shimada I, Takahashi H.

Perdeuteration and methyl-selective 1H, 13C-labeling by using a Kluyveromyces lactis expression system. J Biomol NMR, 57,297-304, (2013). Miyazawa-Ohnami M, Takeuchi K, Takano T, Sugiki T, Shimada I, Takahashi H,

A homogeneous, high-throughput assay for phosphatidylinositol 5-phosphate 4-kinase with a novel, rapid substrate preparation. PLoS One, 8,e54127, (2013). Davis MI, Sasaki AT, Shen M, Emerling BM, Thorne N, Michael S, Pragani R, Boxer M, Sumita K, Takeuchi K, Auld DS, Li Z, Cantley LC, Simenov A.

[Experimental strategy of molecular recognition and application for drug development]. Dozin Bioschience, 291-203, (2013). Takeuchi K, Tokunaga Y, Shimada I.

[Functional regulation mechanism of membrane protein revealed by Solution NMR analysis]. Seibutu Buturi, 53,236-241, (2013). Osawa M, Imai S, Takeuchi K, Shimada I.

2012

Low γ-nuclei detection experiments for bimolecular NMR. Recent Developments in Biomolecular NMR, 25-52, (2012). Takeuchi K, Gal M, Shimada I, Wagner G.

Functional Equilibrium of the KcsA Structure Revealed by NMR. J Biol Chem, 287,39634-39641, (2012). Imai S, Osawa M, Mita K, Toyonaga S, Machiyama A, Ueda T, Takeuchi K, Oiki S, Shimada I.

Functional dynamics of proteins revealed by solution NMR. Curr Opin Struct Biol, 22, 660-669, (2012). Osawa M, Takeuchi K, Ueda T, Nishida N, Shimada I.

Structural Basis for the Golgi Association by the Pleckstrin Homology Domain of the Ceramide Trafficking Protein (CERT). J Biol Chem, 287, 33706-33718, (2012). Sugiki T, Takeuchi K, Yamaji T, Takano T, Tokunaga Y, Kumagai K, Hanada K, Takahashi H, Shimada I.

2011

Speeding up direct 15N detection: hCaN 2D NMR experiment. J Biomol NMR, 51, 497-504, (2011). Gal M, Edmonds KA, Milbradt AG, Takeuchi K, Wagner G.

Protein-ligand docking guided by ligand pharmacophore-mapping experiment by NMR. J Mol Graph Model, 31, 20-27, (2011). Fukunishi Y, Mizukoshi Y, Takeuchi K, Shimada I, Takahashi H, Nakamura H.

Ubiquitination of k-ras enhances activation and facilitates binding to select downstream effectors. Sci Signal, 4, ra13, (2011). Sasaki AT, Carracedo A, Locasale JW, Anastasiou D, Takeuchi K, Kahoud ER, Haviv S, Asara JM, Pandolfi PP, Cantley LC.

Structure of the VP16 transactivator target in the Mediator. Nat Struct Mol Biol, 18, 410-418, (2011). Milbradt AG, Kulkarni M, Yi T, Takeuchi K, Sun ZY, Luna RE, Selenko P, Näär AM, Wagner G.

HNCA-TOCSY-CANH experiments with alternate 13C-12C labeling: a set of 3D experiment with unique supra-sequential information for mainchain resonance assignment. J Biomol NMR, 49, 17-26, (2011). Takeuchi K, Gal M, Takahashi H, Shimada I, Wagner G.

2010

NMR analyses of the Gβγ binding and conformational rearrangements of the cytoplasmic pore of G protein-activated inwardly rectifying potassium channel 1 (GIRK1). J Biol Chem, 286,2215-2223, (2010). Yokogawa M, Osawa M, Takeuchi K, Mase Y, Shimada I.

Distinctive CD3 Heterodimeric Ectodomain Topologies Maximize Antigen-triggered Activation of αβ T Cell Receptors. J Immunol, 185, 2951-2959, (2010). Kim ST, Touma M, Takeuchi K, Sun ZY, Dave VP, Kappes DJ, Wagner G, Reinherz EL.

Nitrogen-detected CAN and CON experiments as alternative experiments for main chain NMR resonance assignments. J Biomol NMR, 47, 271-282, (2010). Takeuchi K, Heffron G, Sun ZY, Frueh DP, Wagner G.

Autoinhibitory interaction in the multidomain adaptor protein Nck: possible roles in improving specificity and functional diversity. Biochemistry, 49,5634-5641, (2010) Takeuchi K, Sun ZY, Park S, Wagner G.

CACA-TOCSY with alternate 13C-12C labeling: a 13Cα direct detection experiment for mainchain resonance assignment, dihedral angle information, and amino acid type identification. J Biomol NMR, 47,55-63, (2010). Takeuchi K, Frueh D, Sun ZY, Hiller S, Wagner G.

Structural basis underlying the dual gate properties of KcsA. Proc Natl Acad Sci, 107,6216-6221, (2010). Imai S, Osawa M, Takeuchi K, Shimada I.

High-resolution 3D CANCA NMR experiments for complete mainchain assignments using C direct-detection. J Am Chem Soc, 132,2945-2951, (2010). Takeuchi K, Frueh D, Hyberts S, Sun ZY, Wagner G.

Poisson-gap sampling and forward maximum entropy reconstruction for enhancing the resolution and sensitivity of protein NMR Data. J Am Chem Soc, 132,2145-2147, (2010). Hyberts SG, Takeuchi K, Wagner G.

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