6376
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2. (a) Behar, S. M.; Porcelli, S. A. Curr. Top. Microbiol. Immun. 2007, 314, 215; (b)
Table 1
H-Bond contacts between iNKT TCR and
a a
-GalCera or -S-GalCer.b,c
Tupin, E.; Kinjo, Y.; Kronenberg, M. Nat. Rev. Microbiol. 2007, 5, 405.
3. (a) Hong, C.; Park, S.-H. Crit. Rev. Immun. 2008, 27, 511; (b) Motohashi, S.;
Nakayama, T. Cancer Sci. 2008, 99, 638; (c) Terabe, M.; Berzofsky, J. A. Trends
Immun. 2007, 28, 491.
4. (a) Meyer, E. H.; DeKruyff, R. H.; Umetsu, D. T. Annu. Rev. Med. 2008, 59, 281; (b)
Yamamura, T.; Sakuishi, K.; Illes, Z.; Miyake, S. J. Neuroimmunol. 2007, 191, 8.
5. Kawano, T.; Cui, J.; Koezuka, Y.; Toura, I.; Kaneko, Y.; Motoki, K.; Ueno, H.;
Nakagawa, R.; Sato, H.; Kondo, E.; Koseki, H.; Taniguchi, M. Science 1997, 278,
1626.
6. Cerundolo, V.; Salio, M. Curr. Top. Microbiol. Immunol. 2007, 314, 325.
7. Kakimi, K.; Guidotti, L. G.; Koezuka, Y.; Chisari, F. V. J. Exp. Med. 2000, 192, 921.
8. (a) Hong, S.; Wilson, M. T.; Serizawa, I.; Wu, I.; Singh, N.; Naidenko, O. V.;
Miura, T.; Haba, T.; Scherer, D. C.; Wei, J.; Kronenberg, M.; Koezuka, Y.; Van
Kaer, L. Nat. Med. 2001, 7, 1052; (b) Sharif, S.; Arreaza, G. A.; Zucker, P.; Mi, Q.
S.; Sondhi, J.; Naidenko, O.; Kronenberg, M.; Koezuka, Y.; Delovitch, T. L.;
Gombert, J. M.; Leite-De-Moraes, M.; Gouarin, C.; Zhu, R.; Hameg, A.;
Nakayama, T.; Taniguchi, M.; Lepault, F.; Leheuh, A.; Bach, J. F.; Herbelin, A.
Nat. Med. 2001, 7, 1057; (c) Wang, B.; Geng, Y. B.; Wang, C. R. J. Exp. Med.
2001, 194, 313; (d) Falcone, M.; Facciotti, F.; Ghidoli, N.; Monti, P.; Olivieri, S.;
Zaccagnino, L.; Bonifacio, E.; Casorati, G.; Sanvito, F.; Sarvetnick, N. J. Immunol.
2004, 172, 5908.
TCR residue
KRN7000
a-S-GalCer
Arg 95
Ser 30
O3
O3
O300
O400
O4
O300
—
d
O400
O400
—
O200,O300
O200
N2
Phe 29
Asp 80
Asp 151
Gly 96
Thr 154
e
—
a
From crystallographic data.
From modeling studies.
For numbering of positions of ligands see Figure 1.
O400 also within H-bonding distance at 2.91 Å.
Loose H-bond.
b
c
d
e
complex with
a-S-GalCer seems to make an additional hydrogen
bond to Asp 80, relative to the complex with KRN7000. However,
three key hydrogen bonds formed between KRN7000 and the pro-
tein appear to either be absent or weakened in the modeled
GalCer/-protein structure.
In the structure with KRN7000, there are two hydrogen bonds
involving Asp 151, a hydrogen bond to the carbonyl of Gly 96 and an-
9. (a) Hansen, D. S.; Siomos, M.-A.; de Koning-Ward, T.; Buckingham, L.; Crabb, B.
S.; Schofield, L. Eur. J. Immunol. 2003, 33, 2588; (b) Gonzalez-Aseguinolaza, G.;
Van Kaer, L.; Bergmann, C. C.; Wilson, J. M.; Schmeig, J.; Kronenberg, M.;
Nakayama, T.; Taniguchi, M.; Koezuka, Y.; Tsuji, M. J. Exp. Med. 2002, 195, 617.
10. Chackerian, A.; Alt, J.; Perera, V.; Behar, S. M. Infect. Immun. 2002, 70, 6302.
11. Zajonc, D. M.; Cantu, C., III; Mattner, J.; Zhou, D.; Savage, P. B.; Bendelac, A.;
Wilson, I. A.; Teyton, L. Nat. Immunol. 2005, 6, 810.
a-S-
12. Koch, M.; Stronge, V. S.; Shepherd, D.; Gadola, S. D.; Matthew, B.; Ritter, G.;
Fersht, A. R.; Besra, G. S.; Schmidt, R. R.; Jones, E. Y.; Cerundolo, V. Nat. Immunol.
2005, 6, 819.
13. Borg, N. A.; Wun, K. S.; Kjer-Nielsen, L.; Wilce, M. C. J.; Pellicci, D. G.; Koh, R.;
Besra, G. S.; Bharadwaj, M.; Godfrey, D. I.; McCluskey, J.; Rossjohn, J. Nature
2007, 448, 44.
14. (a) Fujii, S.-i.; Shimizu, K.; Hemmi, H.; Fukui, M.; Bonito, A. J.; Chen, G.; Franck,
R. W.; Tsuji, M.; Steinman, R. M. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 11252; (b)
Yang, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Angew. Chem. Int. Ed. Engl. 2004,
43, 3818.
15. Schmeig, J.; Yang, G.; Franck, R. W.; Tsuji, M. J. Exp. Med. 2003, 198, 1631.
16. Teng, M. W. L.; Westwood, J. A.; Darcy, P. K.; Sharkey, J.; Tsuji, M.; Franck, R. W.;
Porcelli, S. A.; Besra, G. S.; Takeda, K.; Yagita, H.; Kershaw, M. H.; Smyth, M. J.
Cancer Res. 2007, 67, 7495.
other to the OH of Thr 154. In the
a-S-GalCer complex, only one
hydrogen bond to Asp 151 is detected; however the other would
be possible with a slight shift of Asp 151. There is no hydrogen bond
to Gly 96, due to a shift of both the donor and acceptor atoms. In fact,
thegeometryof a-S-GalCermaypreventtheformationofthishydro-
gen bond. Finally, the hydrogen bond to Thr 154 is weak (3.35 Å) but
may be possible with a slight shift of the threonine. From the model-
ing studies it is not clear why there should be no activation of the
iNKT cells by
to an earlier stage of the iNKT cell activation process. For the
in vivo system degradation or oxidation of the -S-GalCer are possi-
a-S-GalCer. It is likely that the explanation is related
a
17. Dere R, T.; Zhu, X. Org. Lett. 2008, 10, 4641.
bilities. Even in the in vitro assays, loading of the glycolipid onto
CD1d is generally aided by cofactors in the medium.
18. Lyle, F. R. U.S. Patent 6,635,622 B2, 2003 describes
a-S-GalCer and reports
modest anti-tumor activity (based on a lymphocyte mixed culture reaction and
inhibition of metastasis of B16 mouse melanoma cells. Data related to NKT cell
stimulation is not given.
In summary, unlike KRN7000 and the closely related
a-C-Gal-
Cer, -S-GalCer does not stimulate iNKT cells either in vitro or
a
19. (a) Montero, E.; Garcia-Herrero, A.; Asensio, J. L.; Hirai, K.; Ogawa, S.; Santoyo-
Gonzalez, F.; Canada, F. J.; Jimenez-Barbero, J. Eur. J. Org. Chem. 2000, 1945; (b)
Aguilera, B.; Jimenez-Barbero, J.; Fernandez-Mayoralas, A. Carbohydr. Res. 1998,
308, 19; (c) Weimar, T.; Kreis, U. C.; Andrews, J. S.; Pinto, B. M. Carbohydr. Res.
1999, 315, 222.
in vivo under standard conditions. Since reasons for the lack of
activity are not obvious, we are investigating potential
explanations.
20. Hasegawa, A.; Morita, M.; Kojima, Y.; Ishida, H.; Kiso, M. Carbohydr. Res. 1991,
214, 43.
21. Ndonye, R. M.; Izmirian, D. P.; Dunn, M. F.; Yu, K. O. A.; Porcelli, S. A.; Khurana,
A.; Kronenberg, M.; Richardson, S. K.; Howell, A. R. J. Org. Chem. 2005, 70,
10260.
22. Petrov, K. A.; Andreev, L. N. Usp. Khim. 1969, 38, 41.
23. (a) Kaesbeck, L.; Kessler, H. Liebigs Ann. Org. Bioorg. Chem. 1997, 165; (b)
Schmidt, R. R.; Stumpp, M. Liebigs Ann. 1983, 1249.
Acknowledgments
The authors are grateful for financial support provided by NIH
NIAID (AI057519: A.R.H.; 2RO1 AI 45051 and U19 AI046130:
S.B.W.) and JDRF 1-2004-771 to S.B.W.
24. Yamamoto, K.; Watanabe, N.; Matsuda, H.; Oohara, K.; Araya, T.; Hashimoto,
M.; Miyairi, K.; Okazaki, I.; Saito, M.; Shimizu, T.; Kato, H.; Okuno, T. Bioorg.
Med. Chem. Lett. 2005, 15, 4932. The anomeric ratio for 4 was variable, but the
Supplementary data
yield shown is based on the
a-anomer present.
25. Zhu, X.; Schmidt, R. R. Chem. Eur. J. 2004, 10, 875.
26. Godfrey, D. I.; MacDonald, H. R.; Kronenberg, M.; Smyth, M. J.; Van Kaer, L. Nat.
Rev. Immunol. 2004, 4, 231.
Supplementary data associated with this article can be found, in
27. Tsuji, M. Cell. Mol. Life Sci. 2006, 63, 1889.
References and notes
28. For example, see: Forestier, C.; Takaki, T.; Molano, A.; Im, J. S.; Baine, I.; Jerud, E.
S.; Illarionov, P.; Ndonye, R.; Howell, A. R.; Santamaria, P.; Besra, G. S.;
DiLorenzo, T. P.; Porcelli, S. A. J. Immunol. 2007, 178, 1415.
1. Bendelac, A.; Savage, P. A.; Teyton, L. Annu. Rev. Immunol. 2007, 25, 297.