Publication: Resonancia magnética nuclear aplicada al estudio sobre el reconocimiento molecular de ligando con fucosa mediado por el receptor DC-SIGN
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2021-01-28
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Universidad Complutense de Madrid
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Abstract
La presente tesis doctoral se dirige al estudio de la proteína humana DC-SIGN desde una perspectiva estructural, atendiendo a aquellos aspectos que, a nivel molecular, determinan su interacción con sus ligandos de tipo carbohidrato (conformación, interacciones intermoleculares (vdW)…). En concreto, el trabajo aquí expuesto se ha enfocado en el análisis de los procesos de reconocimiento en los que participan ligandos que contienen el monosacárido natural L-fucosa en su estructura. El interés por estudiar dicha proteína se ha acrecentado desde comienzos de este siglo, cuando DC-SIGN fue definitivamente identificada como un receptor de membrana de la familia de las C-type lectins y, más importante, se demostró su implicación directa en los procesos de infección por VIH. A partir de aquí, sucesivos trabajos permitieron subrayar la importancia de este receptor en otros procesos infecciosos que incluían patógenos de todo tipo, ya fueran virus (Ébola), bacterias (M. tuberculosis), hongos (C. albicans) o parásitos (S. mansoni). Desde un punto de vista estructural, es bien sabido que DC-SIGN reconoce e interacciona con oligosacáridos presentes en la superficie externa de estos agentes patógenos. El abanico de oligosacáridos que esta proteína es capaz de reconocer es bastante amplio, aunque es bien sabido que todos ellos contienen fundamentalmente los monosacáridos D-manosa y L-fucosa, con los que interacciona directamente. La interacción con D-manosa ha sido ampliamente estudiada a nivel molecular, especialmente mediante cristalografía de rayos X, lo cual ha permitido disponer de varios modelos que describen con un alto grado de detalle cómo ocurre el reconocimiento de este azúcar y cómo influyen tanto la estructura de la proteína como la del propio oligosacárido en dicho reconocimiento. En cambio, aunque la interacción de DC-SIGN con L-fucosa ha sido estudiada en paralelo, mucha de la información existente referente al reconocimiento de oligosacáridos fucosilados no está completamente justificada desde un punto de vista estructural, lo que ha dificultado en muchos casos la búsqueda de patrones estructurales que permitan entender bien cómo tiene lugar el reconocimiento...
This dissertation is focused on the study of the human protein DC-SIGN, a key lectin involved in the development of diverse pathologies, paying attention to the conformational, dynamics and energy aspects that modulate its interaction with carbohydrate ligands. In particular, the present work has exhaustively analyzed recognition events involving ligands that contain the natural monosaccharide L-fucose. The interest in studying this protein has extensively grown since the beginning of this century. DC-SIGN is a membrane receptor within the C-type lectin family that is directly involved in diverse infectious processes, being HIV one of the most relevant examples described at first. Moreover, it has been also demonstrated its implication in several other pathologic processes involving many different organisms, namely viruses (Ebola), bacteria (M. tuberculosis), fungi (C. albicans) and parasites (S. mansoni). DC-SIGN recognizes those oligosaccharides that coat the external membrane or envelope of the cited pathogens. The range of oligosaccharides that can be recognized by this lectin is fairly wide, although most of them always contain the monosaccharides D-mannose (Man) and L-fucose (Fuc), which directly interact at the primary binding site. The recognition of D-mannose had been widely investigated at a molecular level, especially by using X-Ray crystallography. Thus, this work has concerned the interaction with Fuc-containing antigens, essentially at describing the recognition of the histo blood group antigens A and B from a molecular point of view. These ligands display similar scaffolds with two terminal sugars, one common (L-fucose), and other that is different in each case: D-galactose (Gal, B antigen) or N-acetyl-D-galactosamine (GalNAc, A antigen). Considering the complexity of the system, the project has been undertaken by using Nuclear Magnetic Resonance (NMR) experiments, which have provided essential data both from the receptor´s perspective and from the ligand´s one...
This dissertation is focused on the study of the human protein DC-SIGN, a key lectin involved in the development of diverse pathologies, paying attention to the conformational, dynamics and energy aspects that modulate its interaction with carbohydrate ligands. In particular, the present work has exhaustively analyzed recognition events involving ligands that contain the natural monosaccharide L-fucose. The interest in studying this protein has extensively grown since the beginning of this century. DC-SIGN is a membrane receptor within the C-type lectin family that is directly involved in diverse infectious processes, being HIV one of the most relevant examples described at first. Moreover, it has been also demonstrated its implication in several other pathologic processes involving many different organisms, namely viruses (Ebola), bacteria (M. tuberculosis), fungi (C. albicans) and parasites (S. mansoni). DC-SIGN recognizes those oligosaccharides that coat the external membrane or envelope of the cited pathogens. The range of oligosaccharides that can be recognized by this lectin is fairly wide, although most of them always contain the monosaccharides D-mannose (Man) and L-fucose (Fuc), which directly interact at the primary binding site. The recognition of D-mannose had been widely investigated at a molecular level, especially by using X-Ray crystallography. Thus, this work has concerned the interaction with Fuc-containing antigens, essentially at describing the recognition of the histo blood group antigens A and B from a molecular point of view. These ligands display similar scaffolds with two terminal sugars, one common (L-fucose), and other that is different in each case: D-galactose (Gal, B antigen) or N-acetyl-D-galactosamine (GalNAc, A antigen). Considering the complexity of the system, the project has been undertaken by using Nuclear Magnetic Resonance (NMR) experiments, which have provided essential data both from the receptor´s perspective and from the ligand´s one...
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Tesis inédita de la Universidad Complutense de Madrid. Facultad de Ciencias Químicas, léida el 27-04-2020