記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

In Gram-positive bacteria, sophisticated machineries to acquire the heme group of hemoglobin (Hb) have evolved to extract the precious iron atom contained in it. In the human pathogen Streptococcus pyogenes, the Shr protein is a key component of this machinery. Herein we present the crystal structure of hemoglobin-interacting domain 2 (HID2) of Shr bound to Hb. HID2 interacts with both, the protein and heme portions of Hb, explaining the specificity of HID2 for the heme-bound form of Hb, but not its heme-depleted form. Further mutational analysis shows little tolerance of HID2 to interfacial mutations, suggesting that its interaction surface with Hb could be a suitable candidate to develop efficient inhibitors abrogating the binding of Shr to Hb.

DOI： 10.1038/s41598-024-55734-x

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その他リンク： https://www.nature.com/articles/s41598-024-55734-x

掲載種別：研究論文（学術雑誌）   出版者・発行元：Chemical Science  

Peptoids are a promising drug modality targeting disease-related proteins, but how a peptoid engages in protein binding is poorly understood. This is primarily due to a lack of high-resolution peptoid-protein complex structures and systematic physicochemical studies. Here, we present the first crystal structure of a peptoid bound to a protein, providing high-resolution structural information about how a peptoid binds to a protein. We previously reported a rigid peptoid, oligo(N-substituted alanine) (oligo-NSA), and developed an oligo-NSA-type peptoid that binds to MDM2. X-ray crystallographic analysis of the peptoid bound to MDM2 showed that the peptoid recognizes the MDM2 surface predominantly through the interaction of the N-substituents, while the main chain acts as a scaffold. Additionally, conformational, thermodynamic, and kinetic analysis of the peptoid and its derivatives with a less rigid main chain revealed that rigidification of the peptoid main chain contributes to improving the protein binding affinity. This improvement is thermodynamically attributed to an increased magnitude of the binding enthalpy change, and kinetically to an increased association rate and decreased dissociation rate. This study provides invaluable insights into the design of protein-targeting peptoids.

DOI： 10.1039/d4sc01540a

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Protein Science  

Small molecules that regulate protein–protein interactions can be valuable drugs; however, the development of such small molecules is challenging as the molecule must interfere with an interaction that often involves a large surface area. Herein, we propose that modulating the conformational ensemble of the proteins participating in a given interaction, rather than blocking the interaction by directly binding to the interface, is a relevant strategy for interfering with a protein–protein interaction. In this study, we applied this concept to P-cadherin, a cell surface protein forming homodimers that are essential for cell–cell adhesion in various biological contexts. We first determined the crystal structure of P-cadherin with a small molecule inhibitor whose inhibitory mechanism was unknown. Molecular dynamics simulations suggest that the inhibition of cell adhesion by this small molecule results from modulation of the conformational ensemble of P-cadherin. Our study demonstrates the potential of small molecules altering the conformation ensemble of a protein as inhibitors of biological relevant protein–protein interactions.

DOI： 10.1002/pro.4744

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Chemistry  

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 <italic>via</italic> 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.

DOI： 10.3389/fchem.2021.825669

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：RSC Chemical Biology  

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...

DOI： 10.1039/d1cb00195g

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記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s42003-021-02575-3

記述言語：その他  

DOI： 10.1101/2021.06.15.448612

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.isci.2021.102036

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1021/acs.jmedchem.0c01578

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1021/jacs.9b04371

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1039/c8cc01964a

開催年月日： 2023年7月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：名古屋国際会議場   国名：日本国  

開催年月日： 2023年7月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：名古屋国際会議場   国名：日本国  

開催年月日： 2023年7月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：名古屋国際会議場   国名：日本国  

開催年月日： 2022年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：大阪大学蛋白質研究所   国名：日本国