Presence of carbohydrate binding modules in extracellular region of class C G-protein coupled receptors (C GPCR): An in silico investigation on sweet taste receptor
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Sweet taste receptor (STR) is a C GPCR family member and a suggested drug target for metabolic disorders such as diabetes. Detailed characteristics of the molecule as well as its ligand interactions mode are yet considerably unclear due to experimental study limitations of transmembrane proteins. An in silico study was designed to find the putative carbohydrate binding sites on STR. To this end, α-D-glucose and its α-1,4-oligomers (degree of polymerization up to 14) were chosen as probes and docked into an ensemble of different conformations of the extracellular region of STR monomers (T1R2 and T1R3), using AutoDock Vina. Ensembles had been sampled from an MD simulation experiment. Best poses were further energy-minimized in the presence of water molecules with Amber14 forcefield. For each monomer, four distinct binding regions consisting of one or two binding pockets could be distinguished. These regions were further investigated with regard to hydrophobicity and hydrophilicity of the residues, as well as residue compositions and non-covalent interactions with ligands. Popular binding regions showed similar characteristics to carbohydrate binding modules (CBM). Observation of several conserved or semi-conserved residues in these binding regions suggests a possibility to extrapolate the results to other C GPCR family members. In conclusion, presence of CBM in STR and, by extrapolation, in other C GPCR family members is suggested, similar to previously proposed sites in gut fungal C GPCRs, through transcriptome analyses. STR modes of interaction with carbohydrates are also discussed and characteristics of non-covalent interactions in C GPCR family are highlighted.
Keywordsα-D-glucose carbohydrate binding modules CBM oligomer sweet taste receptor
Nomenclature and abbreviations used
- 3Glc to 14Glc: Ligands
Αlpha-D-glucose will be called glucose, disaccharide composed of two 1,4-α-D-glucoses units maltose and oligomers of 3 to 14 units of glucose will be called 3Glc to 14Glc.
- To clarify characteristics of atomic interactions of oligomers, each pyranose unit is numbered as follows
the first α-D-glucose with its C1 binded to C4 of the next glucose unit is numbered as 1 and others are numbered serially; for example, 3Glc-2 means the second gluco-pyranose unit of the tri-saccharide ligand.
- Other nomenclature adopted by YASARA (software used for docking, please see details in Methods section)
Atoms of each molecule are shown as the name of the molecule or residue followed by the name of the atom; for example, 3Glc-2-O3 means atom O3 of 3Glc-2 and GLY 502-O means oxygen atom of G502.
- Core residues
residues in common between binding pockets located in each distinct region
extracellular part of STR
molecular dynamic simulations
sweet taste receptor
This study was performed as a Ph.D. thesis granted by Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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