title: Characterization of binding properties of ICAM-1 peptides to LFA-1: inhibitors of T-cell adhesion.
abstract: In the present study, we characterized the binding site of two intercellular adhesion molecule-1-derived cyclic peptides, cIBC and cIBR, to the LFA-1 on the surface of T cells. These peptides had been able to inhibit LFA-1/intercellular adhesion molecule-1 signal by blocking the signal-2 of immune synapse. Both peptides prefer to bind to the closed form of LFA-1 I-domain, indicating that two peptides act as allosteric inhibitors against intercellular adhesion molecule-1. Binding site mapping using monoclonal antibodies proposes that cIBC binds to around residues 266-272 of LFA-1 I-domain where this site is adjacent to the metal ion-dependent adhesion site. On the other hand, cIBR binds to the pocket called L-site where is distant from metal ion-dependent adhesion site. Cross-inhibition mapping between two peptides show that cIBR could inhibit the binding of cIBC but not vice versa, suggesting that cIBR has some properties that allow this peptide bind to more than one site. Structural comparison between cIBC and cIBR reveals that cIBR is more flexible than cIBC, allowing this peptide bind to exposed region, such as cIBC-binding site as well as cramped pocket like L-site. Our findings are important for understanding the selectivity of cIBC and cIBR peptides; thus, they can be conjugated with drugs and transported specifically to the target.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave, Lawrence, KS 66047, USA.
authors.forename: Meagan E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Bimo A
authors.initials: BA
authors.lastname: Tejo
authors.forename: Tatyana
authors.initials: T
authors.lastname: Yakovleva
authors.forename: Teruna J
authors.initials: TJ
authors.lastname: Siahaan
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry* / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008954:Models, Biological; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012995:Solubility; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; D010456:Peptides, Cyclic; C515001:cIBC peptide; C515000:cIBR peptide; D018799:Intercellular Adhesion Molecule-1; C016658:phorbolol myristate acetate; D016650:Fluorescein-5-isothiocyanate; D008274:Magnesium; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium