Elucidation of selection mechanism in thymus based on precise estimation of TCR-pMHC binding energy

• Project/Area Number: 25330349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Life / Health / Medical informatics
• Research Institution: Juntendo University
• Principal Investigator: Tsurui Hiromichi 順天堂大学, 医学部, 助教 (40217386)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: T細胞受容体 / 分子動力学 / TCR-pMHC 結合エネルギー / MM/PB(GB)SA / フラグメント分子軌道法 / GPGPU / PIEDA / T細胞受容体 (TCR) / 主要組織適合抗原 (MHC) / 特異的認識 / 結合自由エネルギー / 交差反応性 / FMO / 残基間相互作用 / TCR-pMHC / binding energy / specificity / cross-reactivity / molecular dynamics / 基準振動解析 / homology modeling / binding free energy / MM-PB(GB)SA / AMBER / education in thymus

Outline of Final Research Achievements

MM/PB(GB)SA calculation conditions were searched using co-crystal structures including common pMHC, and TCRs having different binding spectra, 3C5Z (narrow) and 3C60 (broad). Calculated binding free-energy fluctuated within about 30 kCal/mol, too large to the purpose. I exchanged the strategy to understand binding specificity based on precise residue-residue interaction, which are provide by fragment molecular orbital (FMO) method. Five co-crystal structures, 3C5Z, 3C60, 3C6L, 4P5T and 3RDT, having common pMHC and TCRs of different binding spectra were selected. Mutations in the sequence of presented peptide at position 2, 3, 5, 8 with 7, 8, 2 and 3 kinds, respectively, were generated and optimized. FMO calculations were performed for the structures and Pair Interaction Energy Decomposition Analysis (PIEDA) were dene. Detailed analyses of interaction energies between residues of TCR and pMHC were enabled.

Research Products

• [Journal Article] Gray-level co-occurrence matrix analysis of several cell types in mouse brain using resolution-enhanced photothermal microscopy. (2017)
  • Author(s): Takayoshi Kobayashi ; Durga Sundaram ; Kazuaki Nakata ; Hiromichi Tsurui
  • Journal Title: Journal of Biomedical Optics Volume: 22 Issue: 3 Pages: 1-13
  • DOI: 10.1117/1.jbo.22.3.036011
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Biological imaging with nonlinear photothermal microscopy using a compact supercontinuum fiber laser source (2015)
  • Author(s): He J, Miyazaki J, Wang N, Tsurui H, Kobayashi T
  • Journal Title: Optics Express Volume: 23 Issue: 8 Pages: 9762-9771
  • DOI: 10.1364/oe.23.009762
  • Peer Reviewed / Open Access
• [Journal Article] IL-6 signal blockade ameliorates the enhanced osteoclastogenesis and the associated joint destruction in a novel FcγRIIB-deficient rheumatoid arthritis mouse model. (2015)
  • Author(s): Ohtsuji M, Lin Q, Nishikawa K, Ohtsuji N, Okazaki H, Tsurui H, Amano H, Shirai T, Nishimoto N, Nishimura H, and Hirose S.
  • Journal Title: Mod. Rheumatol. Volume: 25 Issue: 2 Pages: 270-277
  • DOI: 10.3109/14397595.2014.950035
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Commensal Bacteria Regulate Thymic Aire Expression (2014)
  • Author(s): Nakajima A, Negishi N, Tsurui H, Kadowaki-Ohtsuji N, Maeda K, Nanno M, Yamaguchi Y, Shimizu N, Yagita H, Okumura K, Habu S.
  • Journal Title: PloS One Volume: 9 Issue: 8 Pages: e105904-e105904
  • DOI: 10.1371/journal.pone.0105904
  • Peer Reviewed / Open Access
• [Journal Article] TNFα but not IL-17 is critical in the pathogenesis of rheumatoid arthritis spontaneously occurring in a unique FcγRIIB-deficient mouse model. (2014)
  • Author(s): Okazaki H, Lin Q, Nishikawa K, Ohtsuji N, Tsurui H, Ohtsuji M, Amano H, Tada N, Sudo K, Nishimura H, Shirai T, and Hirose S.
  • Journal Title: Mod. Rheumatol. Volume: 24 Issue: 6 Pages: 931-938
  • DOI: 10.3109/14397595.2014.886351
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sub-diffraction resolution pump-probe microscopy with shot-noise limited sensitivity using laser diodes (2014)
  • Author(s): Miyazaki, J., Tsurui, H., Hayashi-Takagi, A., Kasai, H. & Kobayashi, T.
  • Journal Title: Opt Express Volume: 22 Issue: 8 Pages: 9024-32
  • DOI: 10.1364/oe.22.009024
  • Peer Reviewed / Open Access
• [Journal Article] TNFa but not IL-17 is critical in the pathogenesis of rheumatoid arthritis spontaneously occurring in a unique FcgRIIB-deficient mouse model. (2014)
  • Author(s): Okazaki H, Lin Q, Nishikawa K, Ohtsuji N, Tsurui H, Ohtsuji M, Amano H, Tada N, Sudo K, Nishimura H, Shirai T, and Hirose S.
  • Journal Title: Mod. Rheumatol. Volume: -
  • Peer Reviewed
• [Journal Article] Phenotype conversion from rheumatoid arthritis to systemic lupus erythematosus by introduction of Yaa mutation into FcgRIIB-deficient C57BL/6 (2013)
  • Author(s): Kawano S, Lin Q, Amano H, Kaneko T, Nishikawa K, Tsurui H, Tada N, Nishimura H,Takai T, Shirai T, Takasaki Y and Hirose S
  • Journal Title: mice. Volume: 43 Issue: 3 Pages: 770-778
  • DOI: 10.1002/eji.201243057
  • Peer Reviewed
• [Journal Article] Exhaustive Characterization of TCR–pMHC Binding Energy Estimated by (2013)
  • Author(s): Tsurui H, Takahashi T, Matsuda Y, Lin Q, Sato-Hayashizaki A, Hirose S
  • Journal Title: General Medicine: Open access Volume: 2 Issue: 01 Pages: 1-7
  • DOI: 10.4172/2327-5146.1000126
  • Peer Reviewed
• [Presentation] T細胞受容体による特異的および交差反応的な抗原認識機構の解明 (2016)
  • Author(s): 土屋裕子、波内良樹、輪湖 博、鶴井博理
  • Organizer: 第５４回日本生物物理学会年会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2016-11-25
• [Presentation] 動的解析に基づく特異性および交差性を有するＴＣＲの高原認識機構の解明 (2016)
  • Author(s): 土屋裕子、波内良樹、輪湖博、鶴井博理
  • Organizer: 第１６回日本タンパク質科学会年会
  • Place of Presentation: 福岡県福岡市
  • Year and Date: 2016-06-07
• [Presentation] Trial to evaluate TCR-pMHC binding free-energy using MM/PB(GB)SA and molecular dynamics (2015)
  • Author(s): Hiromichi Tsurui, Sachiko Hirose
  • Organizer: 第４４回日本免疫学会学術集会
  • Place of Presentation: 北海道 札幌市
  • Year and Date: 2015-11-18
• [Presentation] Characterization of TCR-pMHC interaction based on string model and Miyazawa-Jernigan matrIX (IV) (2014)
  • Author(s): Hiromichi Tsurui, Lin QiNGSHU, Sachiko Hirose
  • Organizer: 第４３回日本免疫学会学術集会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Thorough characterization of TCR-pMHC binding free energy estimated by string model and Miyazawa-Jernigan matrix (III). (2013)
  • Author(s): TSURUI Hiromichi, HIROSE Sachiko.
  • Organizer: 第42回 日本免疫学会総会・学術集会記録
  • Place of Presentation: 幕張
• [Presentation] Blockade of TNFa, but not IL-17, ameliorates spontaneously occurring autoimmune arthritis in FcgRIIB-deficient mice. (2013)
  • Author(s): OKAZAKI Hideki, LIN Qingshun, NISHIKAWA Keiko, TSURUI Hiromichi, OHTSUJI Mareki, NISHIMURA Hiroyuki, SHIRAI Toshikazu, HIROSE Sachiko.
  • Organizer: 第42回 日本免疫学会総会・学術集会記録
  • Place of Presentation: 幕張
• [Presentation] B cell specific deficiency of FcgRIIB results in high levels of autoantibodies without severe lupus nephritis in C57BL/6.Yaa mice. (2013)
  • Author(s): LIN Qingshun, NISHIKAWA Keiko, TSURUI Hiromichi, OKAZAKI Hideki, OHTSUJI Mareki, NISHIMURA Hiroyuki, AMANO Hirofumi, SHIRAI Toshikazu, HIROSE Sachiko.
  • Organizer: 第42回 日本免疫学会総会・学術集会記録
  • Place of Presentation: 幕張
• [Presentation] Peripheral tolerance of antigen-specific Th cells induced with polyethylene glycol-conjugate of protein antigen. (2013)
  • Author(s): OBATA Masaomi, OHTSUJI Mareki, SHIRAI Toshikazu, HIROSE Sachiko, NISHIMURA Hiroyuki.
  • Organizer: 第42回 日本免疫学会総会・学術集会
  • Place of Presentation: 幕張
• [Presentation] Phenotype conversion from rheumatoid arthritis to systemic lupus erythematosus by introduction of Yaa mutation into FcgRIIB-deficient C57BL/6 mice. (2013)
  • Author(s): Sachiko Hirose, Shinya Kawano, Qingshun Lin, Hirofumi Amano, Toshiyuki Kaneko, Keiko Nishikawa, Hiromichi Tsurui, Hiroyuki Nishimura, Toshikazu Shirai.
  • Organizer: 14th International Congress of Immunology,
  • Place of Presentation: Milan, Italy
• [Presentation] Characterization of TCR-pMHC interaction based on string model and Miyazawa-Jernigan matrIX (2013)
  • Author(s): Hiromichi Tsurui, Sachiko Hirose. "
  • Organizer: 14th International Congress of Immunology,
  • Place of Presentation: Milan, Italy
• [Presentation] A novel locus of B6 mice on chromosome 12 plays a role in common process shared by SLE, RA, and Sjögren syndrome. (2013)
  • Author(s): Toshiyuki Kaneko, Hirofumi Amano, Mareki Ohtsuji, Keiko Nishikawa, Shinya Kawano, Naomi Ohtsuji, Qingshun Lin, Hideki Okazaki, Hiromichi Tsurui, Hiroyuki Nishimura, Toshikazu Shirai, Yoshinori Takasaki, and Sachiko Hirose.
  • Organizer: 5th East Asian Group of Rheumatology
  • Place of Presentation: ソウル、韓国