自然免疫系受容体による病原体認識機構の解明

• Project Area: Structural basis of cell-signalling complexes mediating signal perception, transduction and responses
• Project/Area Number: 25121709
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 大戸 梅治 東京大学, 薬学研究科(研究院), 講師 (90451856)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2014: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2013: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
• Keywords: 自然免疫 / Ｘ線結晶構造解析

Outline of Annual Research Achievements

自然免疫は微生物の感染に対する生体の初期防御反応である。微生物の構成成分はToll-like receptors (TLRs)，NOD-like receptors (NLRs)，RIG-I-like receptors (RLRs)などの受容体によって認識されることで様々な免疫応答を引き起こす。これら受容体は，様々な病気の治療薬のターゲットとして注目されている。本課題では，自然免疫系の受容体によるリガンド認識機構やシグナル伝達機構を主にＸ線結晶構造解析により明らかにすることを目的する。
１．核酸認識TLRs (TLR7，TLR8，TLR9)と核酸の複合体（抗ウイルス薬，ワクチン）
２．細胞内NLRs (Nod1，Nod2など)とリガンドの複合体（クローン病，アレルギー）
本年度は、１に関してはTLR8とRNA複合体の結晶構造解析に成功した。さらに、CpG DNAを認識するTLR9の構造解析にも成功した。
２に関してはNod1とNod2の大量調製法の検討を前年度に引き続き行った。その結果、高純度試料の調製に成功し、Nod2に関して構造解析可能な結晶を得ることができた。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Toll-like receptor 8 senses degradation products of single-stranded RNA. (2015)
  • Author(s): Tanji H, Ohto U, Shibata T, Taoka M, Yamauchi Y, Isobe T, Miyake K,
  • Journal Title: Nat Struct Mol Biol. Volume: 22 Issue: 2 Pages: 109-115
  • DOI: 10.1038/nsmb.2943
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Determinants of activity at human Toll-like receptors 7 and 8: quantitative structure-activity (2014)
  • Author(s): Yoo E, Salunke DB, Sil D, Guo X, Salyer AC, Hermanson AR, Kumar M,
  • Journal Title: J Med Chem. Volume: 57 Issue: 19 Pages: 7955-7970
  • DOI: 10.1021/jm500744f
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structural basis of pharmacological chaperoning for human β-galactosidase (2014)
  • Author(s): Suzuki H, et al.
  • Journal Title: J. Biol. Chem. Volume: 289 Issue: 21 Pages: 14560-14568
  • DOI: 10.1074/jbc.m113.529529
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structure-Based Design of Novel Human Toll-like Receptor 8 Agonists. (2014)
  • Author(s): Kokatla, H. P., Sil, D., Tanji, H., Ohto, U., Malladi, S. S., Fox, L. M., Shimizu, T., & David, S. A.
  • Journal Title: ChemMedChem. Volume: 9 Issue: 4 Pages: 713-723
  • DOI: 10.1002/cmdc.201300573
  • Peer Reviewed
• [Journal Article] Structure and function of toll-like receptor 8. (2014)
  • Author(s): Ohto, U., Tanji, H., & Shimizu, T.
  • Journal Title: Microbes Infect. Volume: 16 Issue: 4 Pages: 273-282
  • DOI: 10.1016/j.micinf.2014.01.007
  • Peer Reviewed
• [Journal Article] Impaired α-TTP-PIPs interaction underlies familial vitamin E deficiency. (2013)
  • Author(s): Kono N, Ohto U, Hiramatsu T, Urabe M, Uchida Y, Satow Y, Arai H.
  • Journal Title: Science Volume: 340 Issue: 6136 Pages: 1106-1110
  • DOI: 10.1126/science.1233508
  • NAID: 110009807290
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Serum Amyroid A3 binds MD-2 to activates p38 and NF-kB pathway in a MyD88-dependent manner (2013)
  • Author(s): Deguchi A, Tomita T, Omori T, Komatsu A, Ohto U, Takahashi S, Tanimura N, Akashi-Takamura S, Miyake K, Maru Y
  • Journal Title: J Immunol Volume: 191(4) Issue: 4 Pages: 1856-1864
  • DOI: 10.4049/jimmunol.1201996
  • Peer Reviewed
• [Presentation] Toll様受容体8(TLR8)と一本鎖RNA複合体の結晶構造 (2015)
  • Author(s): 丹治裕美、大戸梅治、柴田琢磨、田岡万悟、山内芳雄、礒邊俊明、三宅健介、清水敏之
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] 自然免疫受容体NOD2の結晶構造解析 (2015)
  • Author(s): 前川早貴子、大戸梅治、清水敏之
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Structural study of Toll-like receptor 8 recognizing viral single stranded RNA (2014)
  • Author(s): Umeharu Ohto
  • Organizer: The International Symposium ‘Molecular basis of host cell competency in virus infection’ 2014
  • Place of Presentation: Yokohama
  • Year and Date: 2014-11-08 – 2014-11-09
  • Invited
• [Presentation] 自然免疫系Toll様受容体の構造生物学研究 (2014)
  • Author(s): 大戸梅治、清水敏之
  • Organizer: 第87回日本生化学会年会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Structural studies of nucleic acid sensing Toll-like receptor (2014)
  • Author(s): U. Ohto, H. Tanji, T. Shibata, K. Miyake, and T. Shimizu
  • Organizer: 23rd Congress and General Assembly of The International Union of Crystallography (IUCr 2014)
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2014-08-05 – 2014-08-12
• [Presentation] TLR8と一本鎖RNAとの複合体の結晶構造 (2014)
  • Author(s): 丹治裕美、大戸梅治、柴田琢磨、三宅健介、清水敏之
  • Organizer: 第14回日本蛋白質科学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-06-25 – 2014-06-27
• [Presentation] Crystal structures of human Toll-like receptor 8 (2013)
  • Author(s): U. Ohto, H. Tanji, T. Shibata, K. Miyake, and T. Shimizu
  • Organizer: 4th International Symposium on Diffraction Structural Biology 2013
  • Place of Presentation: Nagoya
• [Presentation] Structural basis for species-specific endotoxin recognition by TLR4/MD-2 (2013)
  • Author(s): U. Ohto, K. Fukase, K. Miyake, and T. Shimizu
  • Organizer: ICSG2013-SLS
  • Place of Presentation: Sapporo