The creation of co-chaperone HOP inhibitor for cancer therapy.

• Project/Area Number: 25860050
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Sapporo Medical University
• Principal Investigator: YAMAMOTO Soh 札幌医科大学, 医学部, 助教 (10588479)
• Research Collaborator: ITOH Hideaki ; KUBOTA Hiroshi ; YAMAGUCHI Yoshiki ; YOKOTA Shin-ichi
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 分子シャペロン / HSP70 / HSP90 / HOP / タンパク質折りたたみ

Outline of Final Research Achievements

Co-chaperone HOP (HSP70/HSP90 Organizing Protein) assists protein transfer in the HSP70 and HSP90 dependent protein-folding pathway. HOP highly expresses and forms the complexes with HSP70 and HSP90 in cancer cells. In the present study, we investigated (1) identification the inhibitor of HOP for cancer therapy using chemical library and (2) biochemical analysis of ATPase activity of HOP.
(1) We identified binding chemicals to HOP from thirty thousand drugs at first-screening step. We found the twenty-eight drugs that specifically bound to full-length HOP and TPR2A region at secondly-screening step. (2) We determined the ATP hydrolysis rate and dissociation constant, are 3.8 x 10-3mol ATP/mol HOP/min and 350 μM, respectively. 1-359 (TPR1-TPR2A) was required for ATP hydrolysis and interaction with ATP. We demonstrated the HOP changes its conformation by ATP hydrolysis using NMR analysis and protease sensitivity assay.

Research Products

• [Journal Article] Intrafamilial, preferentially mother-to-child and intraspousal, Helicobacter pylori infection in Japan determined by mutilocus sequence typing and random amplified polymorphic DNA fingerprinting (2015)
  • Author(s): Yokota S, Konno M, Fujiwara S, Toita N, Takahashi M, Yamamoto S, Ogasawara N, Shiraishi T
  • Journal Title: Helicobacter Volume: 20 Issue: 5 Pages: 334-342
  • DOI: 10.1111/hel.12217
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structural characterization of the substrate transfer mechanism in Hsp70/Hsp90 folding machinery mediated by Hop (2014)
  • Author(s): Sara Alvira, Jorge Cuéllar, Alina Röhl, Soh Yamamoto, Hideaki Itoh, Carlos B. Alfonso, Germán Rivas, Johannes Buchner, José M. Valpuesta.
  • Journal Title: Nature Communications Volume: 5 Issue: 1 Pages: 1-13
  • DOI: 10.1038/ncomms6484
  • Peer Reviewed
• [Journal Article] Aminoglycosides suppress the protein folding activity of the molecular chaperone HSC70: implication of a structure-activity relationship. (2014)
  • Author(s): Soh Yamamoto, Hideki Wakui, Hiroshi Kubota, Hideaki Itoh, and Shin-ichi Yokota.
  • Journal Title: Chemotherapy Volume: 60 Issue: 1 Pages: 37-46
  • DOI: 10.1159/000365880
  • Peer Reviewed
• [Journal Article] AhR activation mechanisms by molecular chaperone HSP90 (2014)
  • Author(s): Noriko Tsuji, Kana Fukuda, Yuhtaroh Nagata, Hirotaka Okada, Asami Haga, Shiori Hatakeyama, Shiho Yoshida, Tomoya Okamoto, Miki Hosaka, Kazuhiro Sekine, Kei Ohtaka, Soh Yamamoto, Michiro Otaka, Ewa Grave, and Hideaki Itoh.
  • Journal Title: FEBS Open Bio Volume: 16 Issue: 1 Pages: 796-803
  • DOI: 10.1016/j.fob.2014.09.003
  • Peer Reviewed / Open Access
• [Journal Article] 排膿散及湯はインターフェロン産生誘導薬か? (2014)
  • Author(s): 松田三千雄、山本聡、岡林環樹
  • Journal Title: 漢方医学 Volume: 38 Pages: 123-126
• [Journal Article] ATPase activity and ATP-dependent conformational change in the co-chaperone HOP. (2014)
  • Author(s): Yamamoto S, Subedi GP, Hanashima S, Satoh T, Otaka M, Wakui H, Sawada KI, Yokota SI, Yamaguchi Y, Kubota H, Itoh H.
  • Journal Title: Journal of Biological Chemistry Volume: 289 Issue: 14 Pages: 9880-9886
  • DOI: 10.1074/jbc.m114.553255
  • Peer Reviewed
• [Journal Article] Positive relationship between a polymorphism in Helicobacter pylori neutrophil-activating protein A gene and iron-deficiency anemia (2013)
  • Author(s): Yokota S, Toita N, Yamamoto S, Fujii N, Konno M.
  • Journal Title: Ｈｅｌｉｃｏｂａｃｔｅｒ Volume: 18 Issue: 2 Pages: 112-116
  • DOI: 10.1111/hel.12011
  • Peer Reviewed
• [Presentation] アミノグリコシド系抗菌薬による 分子シャペロンHSC70の生理機能阻害 (2014)
  • Author(s): 山本聡、横田伸一
  • Organizer: 第88回日本感染症学会学術講演会 第62回日本化学療法学会総会 合同学会
  • Place of Presentation: ヒルトン福岡シーホーク
  • Year and Date: 2014-06-18 – 2014-06-20
• [Presentation] アミノグリコシド系抗菌薬による分子シャペロンHSC70の生理機能阻害 (2014)
  • Author(s): 山本 聡、横田 伸一
  • Organizer: 第88回日本感染症学会学術講演会 第62回日本化学療法学会総会 合同学会
  • Place of Presentation: 福岡
• [Presentation] Aminoglycoside antibiotics suppress the function of Heat Shock Protein 70. (2013)
  • Author(s): Soh Yamamoto, Shin-ichi Yokota, Hideki Wakui , Hiroshi Kubota, Hideaki Itoh and Nobuhiro Fujii
  • Organizer: The 28th International Congress of Chemotherapy and Infection
  • Place of Presentation: Yokohama