title: Isolated Polar Amino Acid Residues Modulate Lipid Binding in the Large Hydrophobic Cavity of CD1d.
abstract: The CD1d protein is a nonpolymorphic MHC class I-like protein that controls the activation of natural killer T (NKT) cells through the presentation of self- and foreign-lipid ligands, glycolipids, or phospholipids, leading to the secretion of various cytokines. The CD1d contains a large hydrophobic lipid binding pocket: the A' pocket of CD1d, which recognizes hydrophobic moieties of the ligands, such as long fatty acyl chains. Although lipid-protein interactions typically rely on hydrophobic interactions between lipid chains and the hydrophobic sites of proteins, we showed that the small polar regions located deep inside the hydrophobic A' pocket could be used for the modulation of the lipid binding. A series of the ligands, α-galactosyl ceramide (α-GalCer) derivatives containing polar groups in the acyl chain, was synthesized, and the structure-activity relationship studies demonstrated that simple modification from a methylene to an amide group in the long fatty acyl chain, when introduced at optimal positions, enhanced the CD1d recognition of the glycolipid ligands. Formation of hydrogen bonds between the amide group and the polar residues was supported by molecular dynamics (MD) simulations and WaterMap calculations. The computational studies suggest that localized hydrating water molecules may play an important role in the ligand recognition. Here, the results showed that confined polar residues in the large hydrophobic lipid binding pockets of the proteins could be potential targets to modulate the affinity for its ligands.
authors.affiliation: Graduate School of Science and Technology, Keio University , 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Inuki
authors.affiliation: Graduate School of Science and Technology, Keio University , 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.|Graduate School of Science, Osaka University , 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Aiba
authors.affiliation: Graduate School of Science and Technology, Keio University , 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Hirata
authors.affiliation: Schrödinger K. K. , 17F Marunouchi Trust Tower North, 1-8-1 Marunouchi Chiyoda-ku, Tokyo 100-0005, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ichihara
authors.affiliation: Schrödinger K. K. , 17F Marunouchi Trust Tower North, 1-8-1 Marunouchi Chiyoda-ku, Tokyo 100-0005, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yoshidome
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University , Sapporo 060-0812, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kita
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University , Sapporo 060-0812, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Maenaka
authors.affiliation: Graduate School of Science, Osaka University , 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.affiliation: Graduate School of Science and Technology, Keio University , 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Fujimoto
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells; D055610:Antigens, CD1d / Q000737:chemistry*; D001665:Binding Sites; D002478:Cells, Cultured; D018920:Coculture Techniques; D057927:Hydrophobic and Hydrophilic Interactions; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D056004:Molecular Dynamics Simulation; D013154:Spleen / Q000166:cytology / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; D008055:Lipids; D015847:Interleukin-4; D007371:Interferon-gamma