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1 pp. E- -SH X in vitro in vivo -SH Structure-based drug development and medical biological application of cathepsin specific inhibitors Nobuhiko Katunuma Institute for Health Sciences, Tokushima Bunri University,Nishihamabouji, Yamashirocho, Tokushima City, Tokushima, Japan -SH

2 -SH E- V. Turk Huber CA- CA- B Ki M L CLIK- CLIK- S CLIK- K CLIK- CLIK- X M B L S K CA- CA- CLICK- CLIK- CLIK- CLIK- CLIK- CA- CA- B R. Huber D. Turk B X B occluding loop His His C C CA- B CA- CA- B Ki M in vitro in vivo L CLIK- X S CLIK- S S K B K CLIK- CLIK- CLIK- S K E- CA- Sigma CLIK limited proteolysis

3 ９５４生化学第８１巻第１１号図１個々のカテプシン群に対する特異的阻害剤４７図２ CA-０３０のカテプシン B 群に対する特異的結合 X 線共結晶解析による９

4 ２００９年１１月９５５図３ CLIK-１４８のカテプシン L に対する特異的結合 X 線共結晶解析による１９図４抗原提示 T リンパ球のクラススイッチに対するカテプシン類の関与

5 L T Th IgG a IFNγ CLIK- B T Th IgE IgG L- CA- CA- T Th CA- Th Th CLIK- L IgE IgG IL-IgG a IFNγ Th CA- B CA- B Th Th PCA

6 b C T H B a B Z-RR-MCA B MCA -Methyl-Coumaryl- -Amide a - E- µg ml E- µg ml E-µg ml E- µg ml b - CA- µg ml CA- µg ml CA- µg ml CA- µg ml a T C B H B ER B C CA- E-R a B S Sjögren α- α-fodrin CLIK- S α- S CLIK- b

7 a α- T B CLIK- T α- H CLIK- TxNFS non-txnfs NFS b CLIK- S CLIK- CLIK- α- S CLIK- S I L K L K RANCL a

8 a L b CLIK- A CLIK- L TNFα E- CLIK- L TNFα A CLIK-b bioactive receptor S MHC II MHC II B L H

9 L CLIK L Ii L Km Ki M H L B A L CLIK- G.P. Shi L CLIK- - MHC II S IL- -STAT S CLIK- MHC IIα-β Ii L CLIK- - K CLIK- - IgE B CA- CA- CLIK- CLIK- - S CLIK- Turk, V., Turk, B., & Turk, D.EMBO J.,,. Umezawa, H., Morishita, T., Kunimoto, S., & Takeuchi, T. J. Antibiot.,,. Hanada, K., Tamai, M., Yamagishi, M., Ohmura, S., Sawada, J., & Tanaka, I.Agric. Biol. Chem.,,. Murata, M., Miyashita, S., Yokoo, C., Tamai, M., Hanada, K., Hatayama, K., Towatari, T., Nikawa, T., & Katunuma, N. FEBS Lett.,,. Katunuma, N., Murata, E., Kakegawa, H., Matsui, A., Tsuzuki, H., Tsuge, H., Turk, D., Turk, V., Fukushima, M., Tada, Y., & Asao, T.FEBS Lett.,,. Katunuma, N. & Kominami, E.Methods Enzymo.,,. Katunuma, N., Matsui, A., Inubushi, T., Murata, E., Kakegawa, H.,Ohba,Y.,Turk,D.,Turk,V.,Tada,Y.,&Asao,T. Biochem. Biophys. Res. Commun.,,. Musil, D., Zucic, D., Turk, D., Engh, R.A., Mayr, I., Huber,

10 R., Popovic, T., Turk, V., Towatari, T., Katunuma, N., et al. EMBO J.,,. Turk, D., Podobnik, M., Popovic, T., Katunuma, N., Bode, W., Huber, R., & Turk, V.Biochemistry,,. Katunuma, N., Tsuge, H., Nukatsuka, M., Asao, T., & Fukushima, M.Arc. Biochem. Biophys.,,. Matsunaga, Y., Saibara, T., Kido, H., & Katunuma, N. FEBS Lett.,,. Maekawa, Y., Himeno, K., Ishikawa, H., Hisaeda, H., Sakai, T., Dainichi, T., Asao, T., Good, R.A., & Katunuma, N. J. Immunol.,,. Katunuma, N., Kakegawa, H., Matsunaga, Y., & Saibara, T. FEBS Lett.,,. Kamon, H., Sawa, S., Park, S.J., Katunuma, N., Ishihara, K., Murakami, M., & Hirano, T.Immunity,,. Saegusa, K., Ishimaru, N., Yanagi, K., Arakaki, R., Ogawa, K., Saito, I., Katunuma, N., & Hayashi, Y.J. Clin. Invest.,,. Kitamura, H., Kamon, H., Sawa, S., Park, S.J., Katunuma, N., Ishihara, K., Murakami, M., & Hirano, T.Immunity,,. Nagaya, T., Murata, Y., Yamaguchi, S., Nomura, Y., Ohmori, S., Fujieda, M. & Katunuma, N., Yen, P.M., Chin, W.W., & Seo, H.J. Biol. Chem.,,. Yang, M., Zhang, Y., Pan, J., Sun, J., Liu, J., Libby, P., Sukhova, G.K., Doria, A., Katunuma, N., Peroni, O.D., Guerre- Millo, M., Kahn, B.B., Clement, K., & Shi, G-P.Nat. Cell Biol.,,. Tsuge, H., Nishimura, T., Tada, Y., Asao, T., Turk, D., Turk, V., & Katunuma, N.Biochem. Biophys. Res. Commun.,,.

Ł\”ƒ-2005

$Ł\”ƒ-2005$