Details of a Researcher

Personnel Information

写真a

ISHITANI RYUICHIRO

Job title

Professor

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Campus Career 【 display / non-display 】

2024.01

-

2024.09

Tokyo Medical and Dental University， Medical Research Institute， Division of Biological Data Science， -， Professor
2024.10

-

Now

Institute of Science Tokyo， -， Institute of Integrated Research， Biological Data Science， Computational Drug Discovery and Design， Professor
2024.10

-

Now

Institute of Science Tokyo， -， Graduate Schools， Integrative Molecular Biomedicine， Computational Drug Discovery and Design， Professor

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Research Theme 【 display / non-display 】

Development of innovative therapies targeting mitochondrial regulation by one-carbon metabolic enzyme, 2024.09 - 2027.09
Structural biology of membrane transporters involved in the efflux mechanism of organic molecules, 2017.04 - 2020.03

Summary： Living organisms are constantly exposed to toxic organic molecules, and cells have a mechanism to excrete them as a defensive measure. The molecular entity of this efflux mechanism is the membrane protein, the "efflux transporter". In this study, we analyzed the structure of MATE, a multidrug efflux transporter, focusing on the efflux mechanism of organic molecules. For eukaryotic MATE, we determined the structure of the outward opening state of the MATE transporter AtDTX14, from Arabidopsis, and verified the transport mechanism by structure-based mutational analysis. We also analyzed the structure of VcmN, a MATE from a pathogenic bacterium. The results of this structural analysis suggested that VcmN extrudes the substrate by H+-motive force-dependent TM1 bending.
Elucidation of MAPK signaling pathways and biological processes based on mathematical science, 2016.06 - 2021.03

Summary： In mammalian cells, a wide array of extracellular stimuli generates intracellular signals that converge on a limited number of protein kinase cascades, commonly referred to as MAPK pathways. In mammals, there are at least three subfamilies of MAPKs, named p38, JNK, and ERK. While the classical ERK MAPK is mainly activated by mitogenic stimuli, two relatively newly identified MAPKs, p38 and JNK, are preferentially activated by various environmental stresses. Perturbation of these critical signaling systems is involved in a variety of life-threatening diseases, including cancers and autoimmune diseases. In this study, we investigated the regulatory mechanisms and roles of these signaling pathways in cell fate decisions by combining experimental approaches using molecular biology and multi-omics techniques with theoretical approaches based on mathematical science. We also analyzed abnormalities of these signaling pathways in human diseases including cancer and inflammation.
Molecular mechanism of membrane proteins regulated by physical stimuli, 2016.04 - 2021.03

Summary： We elucidated molecular mechanisms of membrane proteins regulated by physical stimuli (light, sound, heat, membrane potential, osmotic pressure). For light perception, we elucidated dynamics of ChR by time-resolved X-ray crystallography. Moreover, we determined the crystal structures of rhodopsin proteins such as Chrimson, HeR, SzR and Rh-PDE, and elucidated molecular mechanisms of their functions. We also determined the structures of Prestin, a voltage-dependent membrane motor protein involved sound amplification, TRPV3 channel sensing heat, voltage-gated potassium channel Kv4 complexed with two regulatory subunits, CALHM ATP channel, voltage-gated Cl- channel VCCN, osmotic pressure-sensing LRRC8 by a single molecular analysis of Cryo-EM, and elucidated their molecular mechanisms.
Structural and functional analyses of organic acid exporters for efficient organic acid production, 2016.04 - 2019.03

Summary： The final goal of our research is the achievement of effective organic acid production with microbial by enhancing the target organic acid efflux. As part of this research, structural and biochemical studies were conducted to reveal the structure and functional mechanism of organic acid exporter. First, to solve the crystal structure of the organic acid exporter, we cloned organic acid transporter genes and homologous genes from micro-bacteria, such as thermophilic bacteria. The cloned organic acid transporters and homologue proteins were expressed in E. coli, and we studied the thermal stability of these proteins. The expressed homologue proteins were purified and we conducted a crystallization screening. As a result, micro-crystals were observed in several conditions.
Structural biology of multidrug transporters, 2013.04 - 2017.03

Summary： Multidrug efflux transporters recognize and export various toxic compounds, thereby conferring antibiotics resistance to the multidrug-resistance pathogens. Understanding of this substrate recognition and export mechanism by multidrug exporters is important from the point of the view of drug discovery. However, the structural analysis of membrane transporters is very difficult. As a result of recent advance of the structural analysis, several crystal structures of multidrug efflux transporters have been determined, but their resolutions were not enough to understand the biologically important aspects, such as the substrate recognition mechanism. In this research project, we performed the structural and functional analyses of YddG, which was initially identified as an efflux pump of toxic compounds, and then shown to export aromatic amino acids by subsequent researches.

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Published Papers & Misc 【 display / non-display 】

Ishitani, R; Takemoto, M; Tomii, K. Protein ligand binding site prediction using graph transformer neural network PLOS ONE. 2024.08; 19 (8): e0308425. ( PubMed, DOI )
Molecular Design Method Using a Reversible Tree Representation of Chemical Compounds and Deep Reinforcement Learning. 2022.09; 62 (17): 4032-4048. ( PubMed, DOI )
Towards universal neural network potential for material discovery applicable to arbitrary combination of 45 elements. 2022.05; 13 (1): 2991. ( PubMed, DOI )
Lateral access mechanism of LPA receptor probed by molecular dynamics simulation. 2022; 17 (2): e0263296. ( PubMed, DOI )
Time-resolved serial femtosecond crystallography reveals early structural changes in channelrhodopsin. 2021.03; 10 ( PubMed, DOI )
Structural biology of the multidrug and toxic compound extrusion superfamily transporters. 2020.12; 1862 (12): 183154. ( PubMed, DOI )
Cryo-EM structure of the volume-regulated anion channel LRRC8D isoform identifies features important for substrate permeation. 2020.05; 3 (1): 240. ( PubMed, DOI )
Identification of Potent In Vivo Autotaxin Inhibitors that Bind to Both Hydrophobic Pockets and Channels in the Catalytic Domain. 2020.03; 63 (6): 3188-3204. ( PubMed, DOI )
Crystal structure of Drosophila Piwi. 2020.02; 11 (1): 858. ( PubMed, DOI )
Author Correction: Structural basis for the drug extrusion mechanism by a MATE multidrug transporter. 2020.02; 578 (7794): E19. ( PubMed, DOI )
Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc. 2019.06; 26 (6): 510-517. ( PubMed, DOI )
Structural basis for oligomerization of the prokaryotic peptide transporter PepTSo2. 2019.05; 75 (Pt 5): 348-358. ( PubMed, DOI )
Structural basis for the promiscuous PAM recognition by Corynebacterium diphtheriae Cas9. 2019.04; 10 (1): 1968. ( PubMed, DOI )
Crystal structure of plant vacuolar iron transporter VIT1. 2019.03; 5 (3): 308-315. ( PubMed, DOI )
Structural Basis of H+-Dependent Conformational Change in a Bacterial MATE Transporter. 2019.02; 27 (2): 293-301. ( PubMed, DOI )
Cap-specific terminal N 6-methylation of RNA by an RNA polymerase II-associated methyltransferase. 2019.01; 363 (6423): ( PubMed, DOI )
Crystal structure of the Agrobacterium tumefaciens type VI effector-immunity complex. 2018.12; 74 (Pt 12): 810-816. ( PubMed, DOI )
Vibrational and Molecular Properties of Mg2+ Binding and Ion Selectivity in the Magnesium Channel MgtE. 2018.10; 122 (42): 9681-9696. ( PubMed, DOI )
Structural insights into cGAMP degradation by Ecto-nucleotide pyrophosphatase phosphodiesterase 1. 2018.10; 9 (1): 4424. ( PubMed, DOI )
An Atomistic Model of a Precursor State of Light-Induced Channel Opening of Channelrhodopsin. 2018.10; 115 (7): 1281-1291. ( PubMed, DOI )
Free Energy Landscape for the Entire Transport Cycle of Triose-Phosphate/Phosphate Translocator. 2018.09; 26 (9): 1284-1296. ( PubMed, DOI )
Engineered CRISPR-Cas9 nuclease with expanded targeting space. 2018.09; 361 (6408): 1259-1262. ( PubMed, DOI )
Cryo-EM structures of the human volume-regulated anion channel LRRC8. 2018.09; 25 (9): 797-804. ( PubMed, DOI )
Functional roles of Mg2+ binding sites in ion-dependent gating of a Mg2+ channel, MgtE, revealed by solution NMR. 2018.04; 7 ( PubMed, DOI )
Structural basis for xenobiotic extrusion by eukaryotic MATE transporter. 2017.11; 8 (1): 1633. ( PubMed, DOI )
Structure of the triose-phosphate/phosphate translocator reveals the basis of substrate specificity. 2017.10; 3 (10): 825-832. ( PubMed, DOI )
Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel. 2017.10; 8 (1): 876. ( PubMed, DOI )
Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6. 2017.08; 548 (7667): 356-360. ( PubMed, DOI )
Structural Basis for the Canonical and Non-canonical PAM Recognition by CRISPR-Cpf1. 2017.08; 67 (4): 633-645. ( PubMed, DOI )
Structural Basis for the Altered PAM Recognition by Engineered CRISPR-Cpf1. 2017.07; 67 (1): 139-147. ( PubMed, DOI )
ATP-dependent modulation of MgtE in Mg2+ homeostasis. 2017.07; 8 (1): 148. ( PubMed, DOI )
Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA. 2017.06; 86 541-566. ( PubMed, DOI )
Structural insights into the nucleotide base specificity of P2X receptors. 2017.03; 7 45208. ( PubMed, DOI )
Crystal Structure of the Minimal Cas9 from Campylobacter jejuni Reveals the Molecular Diversity in the CRISPR-Cas9 Systems. 2017.03; 65 (6): 1109-1121. ( PubMed, DOI )
Correction: Breakpoint Cluster Region-Mediated Inflammation Is Dependent on Casein Kinase II. 2017.01; 198 (2): 971. ( PubMed, DOI )

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Conference Activities & Talks 【 display / non-display 】

Nakamura Ryoki, Kasuya Go, Takemoto Mizuki, Hattori Motoyuki, Ishitani Ryuichiro, Nureki Osamu. MDシミュレーションを用いたATP作動性イオンチャネルP2Xにおける競合的阻害剤TNP-ATPの作用機序の解明(MD simulation of ATP-gated P2X receptors reveals the inhibitory mechanism of a competitive antagonist TNP-ATP). 生物物理 2017.08.01

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Works 【 display / non-display 】

CueMol: Molecular Visualization Framework，Software，2000.01 - Now

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ISHITANI RYUICHIRO

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