| Autor: |
Mukherjee R; Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The Netherlands.; Division of Chemical Biology and Drug Discovery, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The Netherlands., Somovilla VJ; Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramon 182, 20014 Donostia San Sebastián, Spain., Chiodo F; Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Infection and Immunity Research Institute, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands., Bruijns S; Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Infection and Immunity Research Institute, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands., Pieters RJ; Division of Chemical Biology and Drug Discovery, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The Netherlands., Garssen J; Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The Netherlands.; Danone Nutricia Research, Uppsalalaan 12, 3584 CT Utrecht, The Netherlands., van Kooyk Y; Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location Vrije Universiteit, Amsterdam Infection and Immunity Research Institute, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands., Kraneveld AD; Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The Netherlands., van Bergenhenegouwen J; Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, The Netherlands.; Danone Nutricia Research, Uppsalalaan 12, 3584 CT Utrecht, The Netherlands. |
| Abstrakt: |
Human milk oligosaccharides (HMOs) and their most abundant component, 2'-Fucosyllactose (2'-FL), are known to be immunomodulatory. Previously, it was shown that HMOs and 2'-FL bind to the C-type lectin receptor DC-SIGN. Here we show, using a ligand-receptor competition assay, that a whole mixture of HMOs from pooled human milk (HMOS) and 2'-FL inhibit the binding of the carbohydrate-binding receptor DC-SIGN to its prototypical ligands, fucose and the oligosaccharide Lewis-B, (Le b ) in a dose-dependent way. Interestingly, such inhibition by HMOS and 2'-FL was not detected for another C-type lectin, langerin, which is evolutionarily similar to DC-SIGN. The cell-ligand competition assay using DC-SIGN expressing cells confirmed that 2'-FL inhibits the binding of DC-SIGN to Le b . Molecular dynamic (MD) simulations show that 2'-FL exists in a preorganized bioactive conformation before binding to DC-SIGN and this conformation is retained after binding to DC-SIGN. Le b has more flexible conformations and utilizes two binding modes, which operate one at a time via its two fucoses to bind to DC-SIGN. Our hypothesis is that 2'-FL may have a reduced entropic penalty due to its preorganized state, compared to Le b , and it has a lower binding enthalpy, suggesting a better binding to DC-SIGN. Thus, due to the better binding to DC-SIGN, 2'-FL may replace Le b from its binding pocket in DC-SIGN. The MD simulations also showed that 2'-FL does not bind to langerin. Our studies confirm 2'-FL as a specific ligand for DC-SIGN and suggest that 2'-FL can replace other DC-SIGN ligands from its binding pocket during the ligand-receptor interactions in possible immunomodulatory processes. |
