title: Structural basis for ligand recognition in a mushroom lectin: solvent structure as specificity predictor.
abstract: Lectins are able to recognize specific carbohydrate structures through their carbohydrate recognition domain (CRD). The lectin from the mushroom Agaricus bisporus (ABL) has the remarkable ability of selectively recognizing the TF-antigen, composed of Galβ1-3GalNAc, Ser/Thr linked to proteins, specifically exposed in neoplastic tissues. Strikingly, the recently solved crystal structure of tetrameric ABL in the presence of TF-antigen and other carbohydrates showed that each monomer has two CRDs, each being able to bind specifically to different monosaccharides that differ only in the configuration of a single hydroxyl, like N-acetyl-d-galactosamine (GalNAc) and N-acetyl-d-glucosamine (GlcNAc). Understanding how lectin CRDs bind and discriminate mono and/or (poly)-saccharides is an important issue in glycobiology, with potential impact in the design of better and selective lectin inhibitors with potential therapeutic properties. In this work, and based on the unusual monosaccharide epimeric specificity of the ABL CRDs, we have performed molecular dynamics simulations of the natural (crystallographic) and inverted (changing GalNAc for GlcNAc and vice-versa) ABL-monosaccharide complexes in order to understand the selective ligand recognition properties of each CRD. We also performed a detailed analysis of the CRD local solvent structure, using previously developed methodology, and related it with the recognition mechanism. Our results provide a detailed picture of each ABL CRD specificity, allowing a better understanding of the carbohydrate selective recognition process in this particular lectin.
authors: Departamento de Química Inorgánica, Analítica, y Química Física, INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, C1428EHA Ciudad de Buenos Aires, Argentina, Argentina.
authors: Diego F
authors: DF
authors: Gauto
authors: Santiago
authors: S
authors: Di Lella
authors: Darío A
authors: DA
authors: Estrin
authors: Hugo L
authors: HL
authors: Monaco
authors: Marcelo A
authors: MA
authors: Martí
mesh_terms: D000116:Acetylgalactosamine / Q000737:chemistry; D000117:Acetylglucosamine / Q000737:chemistry; D000364:Agaricus / Q000737:chemistry / Q000378:metabolism; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism; D001665:Binding Sites; D002236:Carbohydrate Conformation; D006860:Hydrogen Bonding; D037102:Lectins / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013816:Thermodynamics
chemical_list: C041433:Agaricus lectins; D015295:Antigens, Tumor-Associated, Carbohydrate; D037102:Lectins; C016467:Thomsen-Friedenreich antigen; D000116:Acetylgalactosamine; D000117:Acetylglucosamine