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Akinobu Senoo, Satoru Nagatoishi, Anna Moberg, Linnea Nygren Babol, Tomoya Mitani, Takumi Tashima, Shota Kudo, Kouhei Tsumoto, Inhibition of homophilic dimerization and disruption of cell adhesion by P-cadherin-specific small molecules from SPR-based assays, Chemical Communications, 10.1039/c8cc01964a, 54, 42, 5350-5353, 2018.05, Our SPR-based screening identified a compound which was able to inhibit cell adhesion mediated by homophilic dimerization of P-cadherin. . |
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Jumpei Morimoto, Yasuhiro Fukuda, Daisuke Kuroda, Takumu Watanabe, Fumihiko Yoshida, Mizue Asada, Toshikazu Nakamura, Akinobu Senoo, Satoru Nagatoishi, Kouhei Tsumoto, Shinsuke Sando, A Peptoid with Extended Shape in Water., Journal of the American Chemical Society, 10.1021/jacs.9b04371, 141, 37, 14612-14623, 2019.09, The term "peptoids" was introduced decades ago to describe peptide analogues that exhibit better physicochemical and pharmacokinetic properties than peptides. Oligo(N-substituted glycine) (oligo-NSG) was previously proposed as a peptoid due to its high proteolytic resistance and membrane permeability. However, oligo-NSG is conformationally flexible, and ensuring a defined shape in water is difficult. This conformational flexibility severely limits the biological application of oligo-NSG. Here, we propose oligo(N-substituted alanine) (oligo-NSA) as a peptoid that forms a defined shape in water. The synthetic method established in this study enabled the first isolation and conformational study of optically pure oligo-NSA. Computational simulations, crystallographic studies, and spectroscopic analysis demonstrated the well-defined extended shape of oligo-NSA realized by backbone steric effects. This new class of peptoid achieves the constrained conformation without any assistance of N-substituents and serves as a scaffold for displaying functional groups in well-defined three-dimensional space in water, which leads to effective biomolecular recognition.. |
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Sho Ito, Akinobu Senoo, Satoru Nagatoishi, Masahito Ohue, Masaki Yamamoto, Kouhei Tsumoto, Naoki Wakui, Structural Basis for the Binding Mechanism of Human Serum Albumin Complexed with Cyclic Peptide Dalbavancin., Journal of medicinal chemistry, 10.1021/acs.jmedchem.0c01578, 63, 22, 14045-14053, 2020.11, Cyclic peptides, with unique structural features, have emerged as new candidates for drug discovery; their association with human serum albumin (HSA; long blood half-life) is crucial to improve drug delivery and avoid renal clearance. Here, we present the crystal structure of HSA complexed with dalbavancin, a clinically used cyclic peptide. Small-angle X-ray scattering and isothermal titration calorimetry experiments showed that the HSA-dalbavancin complex exists in a monomeric state; dalbavancin is only bound to the subdomain IA of HSA in solution. Structural analysis and MD simulation revealed that the swing of Phe70 and movement of the helix near dalbavancin were necessary for binding. The flip of Leu251 promoted the formation of the binding pocket with an induced-fit mechanism; moreover, the movement of the loop region including Glu60 increased the number of noncovalent interactions with HSA. These findings may support the development of new cyclic peptides for clinical use, particularly the elucidation of their binding mechanism to HSA.. |
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Tomoki Ota, Akinobu Senoo, Masumi Shirakawa, Hiroshi Nonaka, Yutaro Saito, Sho Ito, Go Ueno, Satoru Nagatoishi, Kouhei Tsumoto, Shinsuke Sando, Structural basis for selective inhibition of human serine hydroxymethyltransferase by secondary bile acid conjugate., iScience, 10.1016/j.isci.2021.102036, 24, 2, 102036-102036, 2021.02, Bile acids are metabolites of cholesterol that facilitate lipid digestion and absorption in the small bowel. Bile acids work as agonists of receptors to regulate their own metabolism. Bile acids also regulate other biological systems such as sugar metabolism, intestinal multidrug resistance, and adaptive immunity. However, numerous physiological roles of bile acids remain undetermined. In this study, we solved the crystal structure of human serine hydroxymethyltransferase (hSHMT) in complex with an endogenous secondary bile acid glycine conjugate. The specific interaction between hSHMT and the ligand was demonstrated using mutational analyses, biophysical measurements, and structure-activity relationship studies, suggesting that secondary bile acid conjugates may act as modulators of SHMT activity.. |
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Akinobu Senoo, Sho Ito, Satoru Nagatoishi, Yutaro Saito, Go Ueno, Daisuke Kuroda, Kouhei Yoshida, Takumi Tashima, Shota Kudo, Shinsuke Sando, Kouhei Tsumoto, Regulation of cadherin dimerization by chemical fragments as a trigger to inhibit cell adhesion, Communications Biology, 10.1038/s42003-021-02575-3, 4, 1, 2021.09, AbstractMany cadherin family proteins are associated with diseases such as cancer. Since cell adhesion requires homodimerization of cadherin molecules, a small-molecule regulator of dimerization would have therapeutic potential. Herein, we describe identification of a P-cadherin-specific chemical fragment that inhibits P-cadherin-mediated cell adhesion. Although the identified molecule is a fragment compound, it binds to a cavity of P-cadherin that has not previously been targeted, indirectly prevents formation of hydrogen bonds necessary for formation of an intermediate called the X dimer and thus modulates the process of X dimerization. Our findings will impact on a strategy for regulation of protein-protein interactions and stepwise assembly of protein complexes using small molecules.. |
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Kaoru Fujimoto, Akinobu Senoo, Satoru Nagatoishi, Daisuke Takahashi, Tadashi Ueda, Kouhei Tsumoto, Jose M.M. Caaveiro, Lipid nanodiscs facilitate the identification of a fragment compound inhibiting the enzymatic activity of the bacterial membrane protein MsbA, 10.1101/2021.06.15.448612, 2021.06, ABSTRACTMembrane proteins are critical elements of numerous therapeutic approaches ranging from cancer to bacterial infections. MsbA is a bacterial membrane protein that has received increasing attention as an antibacterial target for its role in the processing of Lipid A, a key precursor of lipopolysaccharide that is essential for bacterial growth. When employing nanodiscs it is possible to stabilize MsbA by providing a membrane-like environment that enhances its enzymatic activity. Taking advantage of this property we have carried out a fragment screening using the biophysical method of surface plasmon resonance. This approach identified several compounds that bind specifically to MsbA. In particular, one of these fragment molecules not only binds to the target, but also inhibits the ATPase activity of the MsbA protein. The similarity of this fragment to the adenine moiety of ATP points at a route to generate stronger and more potent inhibitors for MsbA and even other proteins of its family of ABC transporters. Collectively, our study reveals biophysical approaches that facilitate the identification of fragment candidates inhibiting the activity of membrane proteins.. |
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Akinobu Senoo, Yutaro Yamada, Kento Ojima, Tomohiro Doura, Itaru Hamachi, Shigeki Kiyonaka, Orthogonal Activation of Metabotropic Glutamate Receptor Using Coordination Chemogenetics, Frontiers in Chemistry, 10.3389/fchem.2021.825669, 9, 2022.01, Cell-surface receptors play a pivotal role as transducers of extracellular input. Although different cell types express the same receptor, the physiological roles of the receptor are highly dependent on cell type. To understand each role, tactics for cell-specific activation of the target receptor are in high demand. Herein, we developed an orthogonal activation method targeting metabotropic glutamate receptor 1 (mGlu1), a G-protein coupled receptor. In this method, direct activation via coordination-based chemogenetics (dA-CBC) was adopted, where activation of mGlu1 was artificially induced by a protein conformational change in response to the coordination of a metal ion or metal-ion complex. Our structure-based protein design and screening approach identified mGlu1 mutants that were directly activated by the coordination of Cu2+ or Zn2+, in addition to our previous Pd-complex-sensitive mGlu1 mutant. Notably, the activation of the mutants was mutually orthogonal, resulting in cell-type selective activation in a model system using HEK293 cells.. |
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Yuta Miura, Akinobu Senoo, Tomohiro Doura, Shigeki Kiyonaka, Chemogenetics of cell surface receptors: beyond genetic and pharmacological approaches, RSC Chemical Biology, 10.1039/d1cb00195g, 2022.01, Cell surface receptors transmit extracellular information into cells. Spatiotemporal regulation of receptor signaling is crucial for cellular functions, and dysregulation of signaling causes various diseases. Thus, it is highly desired.... |
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Akinobu Senoo, Satoru Nagatoishi, Daisuke Kuroda, Sho Ito, Go Ueno, Jose M. M. Caaveiro, Kouhei Tsumoto, Modulation of a conformational ensemble by a small molecule that inhibits key protein-protein interactions involved in cell adhesion., Protein Science, https://doi.org/10.1002/pro.4744, 2023.08. |
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Akinobu Senoo, Masato Hoshino, Toshiki Shiomi, Makoto Nakakido, Satoru Nagatoishi, Daisuke Kuroda, Ichiro Nakagawa, Jeremy R. H. Tame, Jose M. M. Caaveiro, Kouhei Tsumoto, Structural basis for the recognition of human hemoglobin by the heme-acquisition protein Shr from Streptococcus pyogenes, Scientific reports, 10.1038/s41598-024-55734-x, 2024.03. |
