title: Delineating binding modes of Gal/GalNAc and structural elements of the molecular recognition of tumor-associated mucin glycopeptides by the human macrophage galactose-type lectin.
abstract: The human macrophage galactose-type lectin (MGL) is a key physiological receptor for the carcinoma-associated Tn antigen (GalNAc-α-1-O-Ser/Thr) in mucins. NMR and modeling-based data on the molecular recognition features of synthetic Tn-bearing glycopeptides by MGL are presented. Cognate epitopes on the sugar and matching key amino acids involved in the interaction were identified by saturation transfer difference (STD) NMR spectroscopy. Only the amino acids close to the glycosylation site in the peptides are involved in lectin contact. Moreover, control experiments with non-glycosylated MUC1 peptides unequivocally showed that the sugar residue is essential for MGL binding, as is Ca(2+) . NMR data were complemented with molecular dynamics simulations and Corcema-ST to establish a 3D view on the molecular recognition process between Gal, GalNAc, and the Tn-presenting glycopeptides and MGL. Gal and GalNAc have a dual binding mode with opposite trend of the main interaction pattern and the differences in affinity can be explained by additional hydrogen bonds and CH-π contacts involving exclusively the NHAc moiety.
authors.affiliation: REQUIMTE, CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, UNL, 2829-516 Caparica (Portugal); Centro de Investigaciones Biológicas, CIB-CSIC, Ramiro de Maeztu 9, 28040 Madrid (Spain). filipa.marcelo@fct.unl.pt.
authors.forename: Filipa
authors.initials: F
authors.lastname: Marcelo
authors.forename: Fayna
authors.initials: F
authors.lastname: Garcia-Martin
authors.forename: Takahiko
authors.initials: T
authors.lastname: Matsushita
authors.forename: João
authors.initials: J
authors.lastname: Sardinha
authors.forename: Helena
authors.initials: H
authors.lastname: Coelho
authors.forename: Anneloes
authors.initials: A
authors.lastname: Oude-Vrielink
authors.forename: Christiane
authors.initials: C
authors.lastname: Koller
authors.forename: Sabine
authors.initials: S
authors.lastname: André
authors.forename: Eurico J
authors.initials: EJ
authors.lastname: Cabrita
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Nishimura
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Cañada
mesh_terms: D000595:Amino Acid Sequence; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000737:chemistry / Q000378:metabolism*; D006020:Glycopeptides / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type / Q000737:chemistry / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D006020:Glycopeptides; D037181:Lectins, C-Type; C506225:MGL lectin, human; C060192:MUC1 protein, human; D018396:Mucin-1; C040286:Tn antigen
keywords: binding studies; macrophage galactose-type lectin; molecular modeling; molecular recognition; mucin glycopeptides