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Shimamoto K.,Suntory Institute for Bioorganic Research
Bulletin of the Chemical Society of Japan | Year: 2016

Membrane proteins, such as receptors, transporters, and enzymes, play various roles in the survival of organisms. Discovery and development of new bioactive molecules interacting with these proteins are indispensable for understanding the mechanisms of biological events. This account summarizes our efforts on (1) design and synthesis of glutamate transporter blockers to elucidate the mechanism of excitatory neurotransmission process and (2) identification of a novel glycolipid that is essential for membrane protein integration. © 2016 The Chemical Society of Japan. Source


Sugase K.,Suntory Institute for Bioorganic Research
Journal of Biomolecular NMR | Year: 2011

We developed a new method to elucidate the binding kinetics kon and koff, and the dissociation constant KD (=k off/kon), of protein-protein interactions without observable bound resonances of the protein of interest due to high molecular weight in a complex with a large target protein. In our method, kon and koff rates are calculated from the analysis of longitudinal relaxation rates of free resonances measured for multiple samples containing different concentration ratios of 15N-labeled protein and substoichiometric amounts of the target protein. The method is applicable to interactions that cannot be analyzed by relaxation dispersion spectroscopy due to slow interactions on millisecond to second timescale and/or minimal conformational (chemical shift) change upon binding. We applied the method to binding of the B1 domain of protein G (GB1) to immunoglobulin G, and derived the binding kinetics despite the absence of observable bound GB1 resonances. © 2011 Springer Science+Business Media B.V. Source


Takahashi T.,Suntory Institute for Bioorganic Research | Hamaue N.,Health Sciences University of Hokkaido
FEBS Letters | Year: 2010

A full-length cDNA encoding an acetylcholinesterase (AChE) from Hydra magnipapillata was isolated. All of the important aromatic residues that line a catalytic gorge in cholinesterases of other species were conserved, but the sequences of peripheral anionic and choline binding sites were not. Hydra AChE, expressed in Xenopus oocytes, showed AChE activity. The gene was expressed in both ectodermal and endodermal epithelial cells except for the tentacles and basal disk. AChE gene expression was not detected in the regenerating tips in either the head or the foot, indicating that regeneration is controlled by the non-neuronal cholinergic system in Hydra. © 2009 Federation of European Biochemical Societies. Source


Minakata H.,Suntory Institute for Bioorganic Research
Annals of the New York Academy of Sciences | Year: 2010

Recent advances in peptide search methods have revealed two peptide systems that have been conserved through metazoan evolution. Members of the oxytocin/vasopressin-superfamily have been identified from protostomian and deuterostomian animals, indicating that the oxytocin/vasopressin hormonal system represents one of the most ancient systems. In most protostomian animals, a single member of the superfamily shares oxytocin-like and vasopressin-like actions. Co-occurrence of two members has been discovered in modern cephalopods, octopus, and cuttlefish. We propose that cephalopods have developed two peptides in the molluscan evolutionary lineage like vertebrates have established two lineages in the oxytocin/vasopressin superfamily. The existence of gonadotropin-releasing hormone (GnRH) in protostomian animals was initially suggested by immunohistochemical analysis using chordate GnRH antibodies. A peptide with structural features similar to those of chordate GnRHs was originally isolated from octopus, and an identical peptide has been characterized from squid and cuttlefish. Novel forms of GnRH-like molecules from other molluscs, an annelid, arthropods, and nematodes demonstrate somewhat conserved structures at the N-terminal regions; but structures of the C-terminal regions critical to gonadotropin-releasing activity are diverse. These findings may be important for the study of the molecular evolution of GnRH in protostomian animals. © 2010 New York Academy of Sciences. Source


Chung W.J.,Nanyang Technological University | Heddi B.,Nanyang Technological University | Tera M.,Tokyo University of Agriculture and Technology | Tera M.,Suntory Institute for Bioorganic Research | And 3 more authors.
Journal of the American Chemical Society | Year: 2013

Guanine-rich human telomeric DNA can adopt secondary structures known as G-quadruplexes, which can be targeted by small molecules to achieve anticancer effects. So far, the structural information on complexes between human telomeric DNA and ligands is limited to the parallel G-quadruplex conformation, despite the high structural polymorphism of human telomeric G-quadruplexes. No structure has been yet resolved for the complex with telomestatin, one of the most promising G-quadruplex-targeting anticancer drug candidates. Here we present the first high-resolution structure of the complex between an intramolecular (3 + 1) human telomeric G-quadruplex and a telomestatin derivative, the macrocyclic hexaoxazole L2H2-6M(2)OTD. This compound is observed to interact with the G-quadruplex through π-stacking and electrostatic interactions. This structural information provides a platform for the design of topology-specific G-quadruplex-targeting compounds and is valuable for the development of new potent anticancer drugs. © 2013 American Chemical Society. Source

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