Studies on selectin blockers. 4. Structure-function relationships of sulfated sialyl Lewis X hexasaccharide ceramides toward E-, P-, and L-selectin binding.
In order to clarify the real ligand structure of L-selectin proposed by Rosen et al., we first synthesized 6-sulfated sLe(x) hexasaccharide ceramide 1, 6'-sulfated sLe(x) hexasaccharide ceramide 2, and 6,6'-disulfated sLe(x) hexasaccharide ceramide 3 and examined their binding avidities for L-selectin. As a result, we found that the 6'-sulfated sLe(x) hexasaccharide ceramides 1-3 have similar binding avidities to L-selectin and their binding to L-selectin appeared somewhat stronger than that of sLe(x). For P-selectin, the sulfated sLe(x) derivatives 1-3 showed a similar avidity to sLe(x). On the other hand, 6-sulfated sLe(x) 2 was recognized to E-selectin and the binding avidity was apparently weak as compared to that of sLe(x) hexasaccharide ceramide. Surprisingly, 6'-sulfated and 6,6'-disulfated sLe(x)s 1 and 3 did not bind to E-selectin at all. We constructed the E-selectin-sLe(x) complex model and investigated the binding mode. Namely, the galactose 6'-position was directed toward the negatively charged residues, Glu80 and Asp100. Our results with E-selectin indicate that the replacement of 6'-OH position from anionic charged group to cationic charged one, e.g., amino groups, could have a marked affect on E-selectin recognition. These results could provide useful information for the drug design of selectin blockers.
Yoshino
K
K
Department of Biology, Kanebo Institute for Cancer Research, Osaka, Japan.
Ohmoto
H
H
Kondo
N
N
Tsujishita
H
H
Hiramatsu
Y
Y
Inoue
Y
Y
Kondo
H
H
D000818:Animals; D002518:Ceramides / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D019040:E-Selectin / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D019041:L-Selectin / Q000378:metabolism; D007983:Lewis Blood Group Antigens / Q000378:metabolism*; D008956:Models, Chemical; D009844:Oligosaccharides / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism; D051381:Rats; D019087:Selectins / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen; D012984:Software; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013431:Sulfates
D002518:Ceramides; D019040:E-Selectin; D007983:Lewis Blood Group Antigens; D009844:Oligosaccharides; D019007:P-Selectin; D019087:Selectins; D000080506:Sialyl Lewis X Antigen; D013431:Sulfates; D019041:L-Selectin