Selectin-ligand interactions revealed by molecular dynamics simulation in solution

Hideki Tsujishita, Yasuyuki Hiramatsu, Noriko Kondo, Hiroshi Ohmoto, Hirosato Kondo, Makoto Kiso, Akira Hasegawa

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47 Citations (Scopus)


Through a computer modeling and simulation technique, we investigated the binding mode of a complex of E-selectin-GSC-150, which is a novel selectin blocker. GSC-150 is the 3'-sulfated Lewis X derivative with a long, branched alkyl chain. Initial attempts to construct a model for E-selectin- GSC-150 complex were performed based on a previously reported model of E- selectin-sialyl Lewis X (sLe(x)) complex [Kogan, T. P.; Revelle, B. M.; Tapp, S.; Scott, D.; Beck, P. J. J. Biol. Chem. 1995, 270, 14047-14055]. In our model, the carbohydrate portion of GSC-150 interacted with the protein in a similar manner as that of sLe(x) reported previously. Interestingly, each of the branched alkyl chains extended on the surface of E-selectin and interacted with two different hydrophobic portions. One of these hydrophobic portions consists of Tyr44, Pro46, and Tyr48. Another portion forms a shallow cavity, and it consists of Ala9, Leu114, and the alkyl moieties of the side chains of Lys111, Lys112, and Lys113. A subsequent 200-ps molecular dynamics simulation in solution revealed that the interactions involved in the sugar portion of the ligand were relatively weak, whereas the hydrophobic interactions involved in the branched alkyl chains were fairly stable in solution. These results suggest that the branched alkyl chain serves as an 'anchor' for the tight binding of GSC-150 on the surface of E-Selectin. This is the first attempt to evaluate the dynamics of E-Selectin-ligand interactions in solution, and it sheds light on the nature of ligand recognition by selectins.

Original languageEnglish
Pages (from-to)362-369
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number3
Publication statusPublished - Jan 31 1997
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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