The structure and function of the ghrelin receptor coding for drug actions

がん悪液質治療薬アナモレリンが結合したグレリン受容体構造を解明 創薬、個別化医療への道を拓く構造・薬理学情報を拡充. 京都大学プレリリース. 2025-01-21Drugs targeting the ghrelin receptor hold therapeutic potential in anorexia, obesity and diabetes. However, developing effective drugs is challenging. To tackle this common issue across a broad drug target, this study aims to understand how anamorelin, the only approved drug targeting the ghrelin receptor, operates compared to other synthetic drugs. Our research elucidated the receptor's structure with anamorelin and miniGq, unveiling anamorelin's superagonistic activity. We demonstrated that ligands with distinct chemical structures uniquely bind to the receptor, resulting in diverse conformations and biasing signal transduction. Moreover, our study showcased the utility of structural information in effectively identifying natural genetic variations altering drug action and causing severe functional deficiencies, offering a basis for selecting the right medication on the basis of the individual's genomic sequence. Thus, by building on structural analysis, this study enhances the foundational framework for selecting therapeutic agents targeting the ghrelin receptor, by effectively leveraging signaling bias and genetic variations

Structural analysis reveals how tetrameric tyrosine-phosphorylated STAT1 is targeted by the rabies virus P-protein

狂犬病ウイルスが標的とする、四量体pY-STAT1の構造を初めて解明 --STATファミリーに関する新知見の提供および狂犬病に対するワクチン開発の貢献に期待-- . 京都大学プレスリリース. 2025-03-28.Signal transducer and activator of transcription (STAT) family members mediate signaling in the Janus kinase (JAK)-STAT pathway and are activated by phosphorylation at a conserved tyrosine residue, resulting in dimerization through reciprocal interactions between the phosphotyrosine and a Src homology 2 (SH2) domain. Tyrosine-phosphorylated STAT (pY-STAT) then translocates to the nucleus to induce the expression of genes encoding antiviral proteins. Although the active and functional forms of STATs are conventionally considered to be dimers, STATs can undergo higher-order oligomerization, which is implicated in regulating transcriptional activity. We present the cryo-electron microscopy (cryo-EM) structure of the tetrameric form of intact pY-STAT1 in complex with DNA, which indicates that interactions between the amino-terminal domains (NTDs) of STAT1 induce oligomerization. The tetrameric structure revealed a compact conformation with a previously uncharacterized binding interface: Two DNA-bound dimers are twofold symmetrically aligned to transform into a tandem DNA-binding model without NTD dimer separation. Moreover, biochemical analyses indicated that the rabies virus P-protein selectively targeted tetrameric pY-STAT1. Combined with data showing which regions contribute to the interaction between pY-STAT1 and the P-protein, we constructed a binding model explaining how P recognizes the pY-STAT1 tetramer. These data provide insight into how pathogenic viruses target signaling pathways that mediate the host immune response

<MATERIAL>Interview with Former President Risaburo Torikai about Branch School and Purge in Postwar Reform

一九六七年に京都大学が創立七十周年を迎えるにあたり、記念事業の一つとして『京都大学七十年史』が刊行された。本資料は、その資料収集作業の一環で実施された聞き取りの記録であり、鳥養利三郎に総長在任中の出来事についてインタビューを行ったものである

卵巣明細胞癌においてZDHHC7によるYAP1の抑制はフェロトーシス抵抗性と予後不良に関係する

京都大学新制・課程博士博士(医学)甲第25693号医博第5130号新制||医||1076(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 中島 貴子, 教授 永井 洋士, 教授 長船 健二学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

piggyBacシステムを利用したT細胞系列分化可能なアカゲザルiPS細胞における効果的かつ安定的な遺伝子導入法の確立

京都大学新制・課程博士博士(医学)甲第25871号医博第5156号京都大学大学院医学研究科医学専攻(主査)教授 濵﨑 洋子, 教授 遊佐 宏介, 教授 森信 暁雄学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

感情-空間連合が顔表情認識における認知過程に及ぼす影響

京都大学新制・課程博士博士(情報学)甲第26132号情博第907号京都大学大学院情報学研究科知能情報学専攻(主査)教授 熊田 孝恒, 教授 西田 眞也, 准教授 中島 亮一, 佐藤 弥(理化学研究所)学位規則第4条第1項該当Doctor of InformaticsKyoto UniversityDGA

液体アンモニアの蒸発と燃焼に関する数値解析

京都大学新制・課程博士博士(工学)甲第25956号工博第5321号京都大学大学院工学研究科機械理工学専攻(主査)教授 黒瀬 良一, 教授 長田 孝二, 教授 岩井 裕学位規則第4条第1項該当Doctor of Philosophy (Engineering)Kyoto UniversityDFA

Potential-Switchable Viscoelasticity of Protein Nanolayers at a Liquid/Liquid Interface

Protein nanolayers (PNLs) formed at an electrochemical liquid|liquid interface between water (W) and a fluorous solvent (F) were examined by using interfacial rheological measurement (IRM) and neutron reflectometry (NR) under the externally controlled condition of the phase boundary potential differences Fʷ(= φʷ − φF + const.), where F contained a hydrophobic ionic liquid (IL) as a supporting electrolyte and W, whose pH was 7.4, contained a protein, bovine serum albumin (BSA). The IRM and NR results illuminated that both static and dynamic properties of the PNL at the electrochemical F|W interface were varied by applying Fʷ. NR found minimal Fʷ dependence on the adsorption amount of BSA in the PNL. In contrast, IRM revealed that although the interfacial shear loss moduli ″ of the PNL was constant regardless of Fʷ, the interfacial shear storage ′ of the PNL increased dramatically at more negative Fʷ, showing a more elastic response. This difference between static and dynamic properties results from the increase in intermolecular and intramolecular interactions between BSA molecules in the PNL at more negative Fʷ due to the accelerated denaturation of negatively charged BSA that formed complexes with IL cations accumulated on the F side of the F|W interface. The ′ and ″ reversibly responded to switching between different potentials (a positive and a negative Fʷ). These IRM results unveiled that the viscoelasticity of the PNL at the electrochemical F|W interface is reversibly potential-switchable. The present interface-specific method using the potential control is a new promising method to diversify and switch the PNL structure reversibly. The reversible structural control of the PNL would enable us to perform real-time observation of cells reacting to environmental changes at liquid|liquid interfaces