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7. Photoresponsive Adenosine Derivatives for the Optical Control of Adenosine A2AReceptors in Living Cells

Author

Suzuki, Harufumi, Doura, Tomohiro, Matsuba, Yuya, Matsuoka, Yuma, Araya, Tsuyoshi, Asada, Hidetsugu, Iwata, So, and Kiyonaka, Shigeki

Abstract

The use of photoresponsive ligands to optically control proteins of interest, known as photopharmacology, is a powerful technique for elucidating cellular function in living cells and animals with a high spatiotemporal resolution. The adenosine A2Areceptor (A2AR) is a G protein-coupled receptor that is expressed in various tissues; its dysregulation is implicated in severe diseases such as insomnia and Parkinson’s disease. A detailed elucidation of the physiological function of A2AR is, therefore, highly desirable. In the present study, we developed two photoswitchable ligands, photoAd(blue) and photoAd(vio), that target A2AR. Using photoAd(vio), we successfully demonstrated the selective activation of A2AR in living cells by violet-light irradiation with high spatiotemporal resolution.

Published
2024
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9. Neurotransmitter recognition by human vesicular monoamine transporter 2

Author

50721883, 00734469, 60452330, Im, Dohyun, Jormakka, Mika, Juge, Narinobu, Kishikawa, Jun-ichi, Kato, Takayuki, Sugita, Yukihiko, Noda, Takeshi, Uemura, Tomoko, Shiimura, Yuki, Miyaji, Takaaki, Asada, Hidetsugu, Iwata, So, 50721883, 00734469, 60452330, Im, Dohyun, Jormakka, Mika, Juge, Narinobu, Kishikawa, Jun-ichi, Kato, Takayuki, Sugita, Yukihiko, Noda, Takeshi, Uemura, Tomoko, Shiimura, Yuki, Miyaji, Takaaki, Asada, Hidetsugu, and Iwata, So

Abstract

Human vesicular monoamine transporter 2 (VMAT2), a member of the SLC18 family, plays a crucial role in regulating neurotransmitters in the brain by facilitating their uptake and storage within vesicles, preparing them for exocytotic release. Because of its central role in neurotransmitter signalling and neuroprotection, VMAT2 is a target for neurodegenerative diseases and movement disorders, with its inhibitor being used as therapeutics. Despite the importance of VMAT2 in pharmacophysiology, the molecular basis of VMAT2-mediated neurotransmitter transport and its inhibition remains unclear. Here we show the cryo-electron microscopy structure of VMAT2 in the substrate-free state, in complex with the neurotransmitter dopamine, and in complex with the inhibitor tetrabenazine. In addition to these structural determinations, monoamine uptake assays, mutational studies, and pKa value predictions were performed to characterize the dynamic changes in VMAT2 structure. These results provide a structural basis for understanding VMAT2-mediated vesicular transport of neurotransmitters and a platform for modulation of current inhibitor design.

Published
2024

10. Dual 5‑HT2A and 5‑HT2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.

Author

Oguma, Takuya, Jino, Kohei, Nakahara, Kenji, Asada, Hidetsugu, Fuchino, Kouki, Nagatani, Kotaro, Kouki, Kensuke, Okamoto, Ryuji, Takai, Nozomi, Koda, Ken, Fujita, Sayaka, Sekiguchi, Yusuke, Yasuo, Kazuya, Mayumi, Kei, Abe, Ayane, Imono, Masaaki, Horiguchi, Naotaka, Iwata, So, and Kusakabe, Ken-ichi

Published
2024
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13. Dual 5-HT2Aand 5-HT2CReceptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis

Author

Oguma, Takuya, Jino, Kohei, Nakahara, Kenji, Asada, Hidetsugu, Fuchino, Kouki, Nagatani, Kotaro, Kouki, Kensuke, Okamoto, Ryuji, Takai, Nozomi, Koda, Ken, Fujita, Sayaka, Sekiguchi, Yusuke, Yasuo, Kazuya, Mayumi, Kei, Abe, Ayane, Imono, Masaaki, Horiguchi, Naotaka, Iwata, So, and Kusakabe, Ken-ichi

Abstract

Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson’s disease psychosis, pimavanserin (1), a 5-HT2Areceptor inverse agonist having minimal 5-HT2Creceptor affinity and no dopamine D2receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT2Aand 5-HT2Creceptor inverse agonist 8having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2Aand 5-HT2Creceptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2Aand 5-HT2Coccupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2Caffinity in 1followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8that showed significant antipsychotic efficacy due to the involvement of both receptors.

Published
2024
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19. Structural insights into the agonists binding and receptor selectivity of human histamine H₄ receptor

Author

50721883, 00734469, 00422410, 20399041, 60452330, Im, Dohyun, Kishikawa, Jun-ichi, Shiimura, Yuki, Hisano, Hiromi, Ito, Akane, Fujita-Fujiharu, Yoko, Sugita, Yukihiko, Noda, Takeshi, Kato, Takayuki, Asada, Hidetsugu, Iwata, So, 50721883, 00734469, 00422410, 20399041, 60452330, Im, Dohyun, Kishikawa, Jun-ichi, Shiimura, Yuki, Hisano, Hiromi, Ito, Akane, Fujita-Fujiharu, Yoko, Sugita, Yukihiko, Noda, Takeshi, Kato, Takayuki, Asada, Hidetsugu, and Iwata, So

Abstract

Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H₄ receptor (H₄R) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the H₄R-Gq complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe344[7.39], which, in turn, form the “aromatic slot”. The results provide insights into the molecular underpinnings of the agonism of H₄R and subtype selectivity of histamine receptors, and show that the H₄R structures may be valuable in rational drug design of drugs targeting the H₄R.

Published
2023

20. Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor.

Author

Im, Dohyun, Kishikawa, Jun-ichi, Shiimura, Yuki, Hisano, Hiromi, Ito, Akane, Fujita-Fujiharu, Yoko, Sugita, Yukihiko, Noda, Takeshi, Kato, Takayuki, Asada, Hidetsugu, and Iwata, So

Subjects
HISTAMINE receptors, DRUG design, OPIOID receptors, BIOGENIC amines, ATOPIC dermatitis, INFLAMMATION, STRUCTURAL design
Abstract

Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H4 receptor (H4R) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the H4R-Gq complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe3447.39, which, in turn, form the "aromatic slot". The results provide insights into the molecular underpinnings of the agonism of H4R and subtype selectivity of histamine receptors, and show that the H4R structures may be valuable in rational drug design of drugs targeting the H4R. Histamine receptor H4R is implicated in chronic inflammatory diseases, such as asthma, arthritis, and atopic dermatitis. Here, the authors determined the first cryo-EM structure of the histamine H4 receptor, providing valuable structural insights for the design of drugs targeting H4R in chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Published
2023
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26. Endogenous agonist–bound S1PR3 structure reveals determinants of G protein–subtype bias

Author

Maeda, Shintaro, Shiimura, Yuki, Asada, Hidetsugu, Hirata, Kunio, Luo, Fangjia, Nango, Eriko, Tanaka, Nobuo, Toyomoto, Masayasu, Inoue, Asuka, Aoki, Junken, Iwata, So, and Hagiwara, Masatoshi

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the “quartet core”) exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein–coupled receptors and will help the design of biased ligands for optimized therapeutics., 脂質受容体の新たな活性化機構を解明 --脂質がまっすぐ伸びて活性化--. 京都大学プレスリリース. 2021-06-10.

Published
2021

27. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist

Author

Haga, Kazuko, Kruse, Andrew C., Asada, Hidetsugu, Yurugi-Kobayashi, Takami, Shiroishi, Mitsunori, Zhang, Cheng, Weis, William I., Okada, Tetsuji, Kobilka, Brian K., Haga, Tatsuya, and Kobayashi, Takuya

Subjects
Structure, Physiological aspects, Research, G proteins -- Physiological aspects -- Research, Muscarinic receptors -- Structure -- Research, Binding proteins -- Physiological aspects -- Research
Abstract

Muscarinic receptors constitute a family with five subtypes, M1-M5 (ref. 1). M1, M3 and M5 subtypes couple with the [G.sub.q] family of G proteins, and M2 and M4 subtypes with [...], The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves (1-5). Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.

Published
2012
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31. Endogenous agonist–bound S1PR3 structure reveals determinants of G protein–subtype bias

Author

20399041, 20600505, 60452330, 10208423, Maeda, Shintaro, Shiimura, Yuki, Asada, Hidetsugu, Hirata, Kunio, Luo, Fangjia, Nango, Eriko, Tanaka, Nobuo, Toyomoto, Masayasu, Inoue, Asuka, Aoki, Junken, Iwata, So, Hagiwara, Masatoshi, 20399041, 20600505, 60452330, 10208423, Maeda, Shintaro, Shiimura, Yuki, Asada, Hidetsugu, Hirata, Kunio, Luo, Fangjia, Nango, Eriko, Tanaka, Nobuo, Toyomoto, Masayasu, Inoue, Asuka, Aoki, Junken, Iwata, So, and Hagiwara, Masatoshi

Abstract

Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the “quartet core”) exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein–coupled receptors and will help the design of biased ligands for optimized therapeutics.

Published
2021

39. Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone

Author

50721883, 20399041, 10314246, 60452330, 90391979, Im, Dohyun, Inoue, Asuka, Fujiwara, Takaaki, Nakane, Takanori, Yamanaka, Yasuaki, Uemura, Tomoko, Mori, Chihiro, Shiimura, Yuki, Kimura Terakado, Kanako, Asada, Hidetsugu, Nomura, Norimichi, Tanaka, Tomoyuki, Yamashita, Ayumi, Nango, Eriko, Tono, Kensuke, Kadji, Francois Marie Ngako, Aoki, Junken, Iwata, So, Shimamura, Tatsuro, 50721883, 20399041, 10314246, 60452330, 90391979, Im, Dohyun, Inoue, Asuka, Fujiwara, Takaaki, Nakane, Takanori, Yamanaka, Yasuaki, Uemura, Tomoko, Mori, Chihiro, Shiimura, Yuki, Kimura Terakado, Kanako, Asada, Hidetsugu, Nomura, Norimichi, Tanaka, Tomoyuki, Yamashita, Ayumi, Nango, Eriko, Tono, Kensuke, Kadji, Francois Marie Ngako, Aoki, Junken, Iwata, So, and Shimamura, Tatsuro

Abstract

In addition to the serotonin 5-HT2A receptor (5-HT2AR), the dopamine D2 receptor (D2R) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of D2R have been described in complex with the inverse agonists risperidone (D2Rris) and haloperidol (D2Rhal). Here we describe the structure of human D2R in complex with spiperone (D2Rspi). In D2Rspi, the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in D2Rris and D2Rhal, demonstrating that ECL2 in D2R is highly dynamic. Moreover, D2Rspi exhibited an extended binding pocket to accommodate spiperone’s phenyl ring, which probably contributes to the selectivity of spiperone to D2R and 5-HT2AR. Together with D2Rris and D2Rhal, the structural information of D2Rspi should be of value for designing novel antipsychotics with improved safety and efficacy.

Published
2020

44. Platform for the rapid construction and evaluation of GPCRs for crystallography in Saccharomyces cerevisiae

Author

Shiroishi Mitsunori, Tsujimoto Hirokazu, Makyio Hisayoshi, Asada Hidetsugu, Yurugi-Kobayashi Takami, Shimamura Tatsuro, Murata Takeshi, Nomura Norimichi, Haga Tatsuya, Iwata So, and Kobayashi Takuya

Subjects
G-protein coupled receptor, Membrane protein, High expression, Screening, Receptor variants, Structural study, Saccharomyces cerevisiae, Microbiology, QR1-502
Abstract

Abstract Background Recent successes in the determination of G-protein coupled receptor (GPCR) structures have relied on the ability of receptor variants to overcome difficulties in expression and purification. Therefore, the quick screening of functionally expressed stable receptor variants is vital. Results We developed a platform using Saccharomyces cerevisiae for the rapid construction and evaluation of functional GPCR variants for structural studies. This platform enables us to perform a screening cycle from construction to evaluation of variants within 6–7 days. We firstly confirmed the functional expression of 25 full-length class A GPCRs in this platform. Then, in order to improve the expression level and stability, we generated and evaluated the variants of the four GPCRs (hADRB2, hCHRM2, hHRH1 and hNTSR1). These stabilized receptor variants improved both functional activity and monodispersity. Finally, the expression level of the stabilized hHRH1 in Pichia pastoris was improved up to 65 pmol/mg from negligible expression of the functional full-length receptor in S. cerevisiae at first screening. The stabilized hHRH1 was able to be purified for use in crystallization trials. Conclusions We demonstrated that the S. cerevisiae system should serve as an easy-to-handle and rapid platform for the construction and evaluation of GPCR variants. This platform can be a powerful prescreening method to identify a suitable GPCR variant for crystallography.

Published
2012
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45. Evaluation of the Pichia pastoris expression system for the production of GPCRs for structural analysis

Author

Sugawara Taishi, Ito Keisuke, Tsujimoto Hirokazu, Shimamura Tatsuro, Shiroishi Mitsunori, Yurugi-Kobayashi Takami, Uemura Tomoko, Asada Hidetsugu, Nakane Takanori, Nomura Norimichi, Murata Takeshi, Haga Tatsuya, Iwata So, and Kobayashi Takuya

Subjects
Microbiology, QR1-502
Abstract

Abstract Background Various protein expression systems, such as Escherichia coli (E. coli), Saccharomyces cerevisiae (S. cerevisiae), Pichia pastoris (P. pastoris), insect cells and mammalian cell lines, have been developed for the synthesis of G protein-coupled receptors (GPCRs) for structural studies. Recently, the crystal structures of four recombinant human GPCRs, namely β2 adrenergic receptor, adenosine A2a receptor, CXCR4 and dopamine D3 receptor, were successfully determined using an insect cell expression system. GPCRs expressed in insect cells are believed to undergo mammalian-like posttranscriptional modifications and have similar functional properties than in mammals. Crystal structures of GPCRs have not yet been solved using yeast expression systems. In the present study, P. pastoris and insect cell expression systems for the human muscarinic acetylcholine receptor M2 subtype (CHRM2) were developed and the quantity and quality of CHRM2 synthesized by both expression systems were compared for the application in structural studies. Results The ideal conditions for the expression of CHRM2 in P. pastoris were 60 hr at 20°C in a buffer of pH 7.0. The specific activity of the expressed CHRM2 was 28.9 pmol/mg of membrane protein as determined by binding assays using [3H]-quinuclidinyl benzilate (QNB). Although the specific activity of the protein produced by P. pastoris was lower than that of Sf9 insect cells, CHRM2 yield in P. pastoris was 2-fold higher than in Sf9 insect cells because P. pastoris was cultured at high cell density. The dissociation constant (Kd) for QNB in P. pastoris was 101.14 ± 15.07 pM, which was similar to that in Sf9 insect cells (86.23 ± 8.57 pM). There were no differences in the binding affinity of CHRM2 for QNB between P. pastoris and Sf9 insect cells. Conclusion Compared to insect cells, P. pastoris is easier to handle, can be grown at lower cost, and can be expressed quicker at a large scale. Yeast, P. pastoris, and insect cells are all effective expression systems for GPCRs. The results of the present study strongly suggested that protein expression in P. pastoris can be applied to the structural and biochemical studies of GPCRs.

Published
2011
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48. Ligand binding to human prostaglandin E receptor EP4 at the lipid-bilayer interface

Author

Toyoda, Yosuke, primary, Morimoto, Kazushi, additional, Suno, Ryoji, additional, Horita, Shoichiro, additional, Yamashita, Keitaro, additional, Hirata, Kunio, additional, Sekiguchi, Yusuke, additional, Yasuda, Satoshi, additional, Shiroishi, Mitsunori, additional, Shimizu, Tomoko, additional, Urushibata, Yuji, additional, Kajiwara, Yuta, additional, Inazumi, Tomoaki, additional, Hotta, Yunhon, additional, Asada, Hidetsugu, additional, Nakane, Takanori, additional, Shiimura, Yuki, additional, Nakagita, Tomoya, additional, Tsuge, Kyoshiro, additional, Yoshida, Suguru, additional, Kuribara, Tomoko, additional, Hosoya, Takamitsu, additional, Sugimoto, Yukihiko, additional, Nomura, Norimichi, additional, Sato, Miwa, additional, Hirokawa, Takatsugu, additional, Kinoshita, Masahiro, additional, Murata, Takeshi, additional, Takayama, Kiyoshi, additional, Yamamoto, Masaki, additional, Narumiya, Shuh, additional, Iwata, So, additional, and Kobayashi, Takuya, additional

Published
2018
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49. Proteoliposome-based Selection of a Recombinant Antibody Fragment Against the Human M2 Muscarinic Acetylcholine Receptor.

Author

20399041, 90391979, 60452330, 10314246, Suharni, Nomura, Yayoi, Arakawa, Takatoshi, Hino, Tomoya, Abe, Hitomi, Nakada-Nakura, Yoshiko, Sato, Yumi, Iwanari, Hiroko, Shiroishi, Mitsunori, Asada, Hidetsugu, Shimamura, Tatsuro, Murata, Takeshi, Kobayashi, Takuya, Hamakubo, Takao, Iwata, So, Nomura, Norimichi, 20399041, 90391979, 60452330, 10314246, Suharni, Nomura, Yayoi, Arakawa, Takatoshi, Hino, Tomoya, Abe, Hitomi, Nakada-Nakura, Yoshiko, Sato, Yumi, Iwanari, Hiroko, Shiroishi, Mitsunori, Asada, Hidetsugu, Shimamura, Tatsuro, Murata, Takeshi, Kobayashi, Takuya, Hamakubo, Takao, Iwata, So, and Nomura, Norimichi

Abstract

The development of antibodies against human G-protein-coupled receptors (GPCRs) has achieved limited success, which has mainly been attributed to their low stability in a detergent-solubilized state. We herein describe a method that can generally be applied to the selection of phage display libraries with human GPCRs reconstituted in liposomes. A key feature of this approach is the production of biotinylated proteoliposomes that can be immobilized on the surface of streptavidin-coupled microplates or paramagnetic beads and used as a binding target for antibodies. As an example, we isolated a single chain Fv fragment from an immune phage library that specifically binds to the human M2 muscarinic acetylcholine receptor with nanomolar affinity. The selected antibody fragment recognized the GPCR in both detergent-solubilized and membrane-embedded forms, which suggests that it may be a potentially valuable tool for structural and functional studies of the GPCR. The use of proteoliposomes as immunogens and screening bait will facilitate the application of phage display to this difficult class of membrane proteins.

Published
2014

50. Structures of the 5-HT2Areceptor in complex with the antipsychotics risperidone and zotepine

Author

Kimura, Kanako Terakado, Asada, Hidetsugu, Inoue, Asuka, Kadji, Francois Marie Ngako, Im, Dohyun, Mori, Chihiro, Arakawa, Takatoshi, Hirata, Kunio, Nomura, Yayoi, Nomura, Norimichi, Aoki, Junken, Iwata, So, and Shimamura, Tatsuro

Abstract

Many drugs target the serotonin 2A receptor (5-HT2AR), including second-generation antipsychotics that also target the dopamine D2receptor (D2R). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HT2AR in complex with the second-generation antipsychotics risperidone and zotepine. These antipsychotics effectively stabilize the inactive conformation by forming direct contacts with the residues at the bottom of the ligand-binding pocket, the movements of which are important for receptor activation. 5-HT2AR is structurally similar to 5-HT2CR but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HT2AR-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HT2AR significantly differs around extracellular loops 1 and 2 from that in D2R. These findings are beneficial for the rational design of safer antipsychotics and 5-HT2AR-selective drugs.

Published
2019
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