Atomistic mechanisms underlying the activation of the G protein-coupled sweet receptor heterodimer by sugar alcohol recognition

Abstract

The human T1R2-T1R3 sweet taste receptor (STR) plays an important role in recognizing various low-molecular-weight sweet-tasting sugars and proteins, resulting in the release of intracellular heterotrimeric G protein that in turn leads to the sweet taste perception. Xylitol and sorbitol, which are naturally occurring sugar alcohols (polyols) found in many fruits and vegetables, exhibit the potential caries-reducing effect and are widely used for diabetic patients as low-calorie sweeteners. In the present study, computational tools were applied to investigate the structural details of binary complexes formed between these two polyols and the T1R2-T1R3 heterodimeric STR. Principal component analysis revealed that the Venus flytrap domain (VFD) of T1R2 monomer was adapted by the induced-fit mechanism to accommodate the focused polyols, in which residues 233–268 moved significantly closer to stabilize ligands. This finding likely suggested that these structural transformations might be the important mechanisms underlying polyols-STR recognitions. The calculated free energies also supported the VFD of T1R2 monomer as the preferential binding site for such polyols, rather than T1R3 region, in accord with the lower number of accessible water molecules in the T1R2 pocket. The E302 amino acid residue in T1R2 was found to be the important recognition residue for polyols binding through a strongly formed hydrogen bond. Additionally, the binding affinity of xylitol toward the T1R2 monomer was significantly higher than that of sorbitol, making it a sweeter tasting molecule.

Structural insight into the recognition of S-adenosyl-L-homocysteine and sinefungin in SARS-CoV-2 Nsp16/Nsp10 RNA cap 2′-O-Methyltransferase

“…7 B-C , the SASAs for the apo protein (chain B, pale green) were 829.43 ± 32.47 and 864.07 ± 38.86 Å 2 for SAH and SFG systems, respectively. Upon molecular complexation with the nucleoside analogs (chain A, dark green), the SASAs of both models tremendously decreased by ∼200 to 350 Å 2 , consistent well with the reported SASA loss during the binding process from other works [51] , [52] , [53] . It is worth noting that the SFG model (507.03 ± 25.45 Å 2 ) exhibited lower SASAs than the SAH system (589.70 ± 30.03 Å 2 ), indicating that the binding efficiency of SFG is greater than that of SAH, as evidenced by the Δ G bind calculations ( Table 1 ).…”

Computational study on peptidomimetic inhibitors against SARS-CoV-2 main protease

“…Once the inhibitor bound to the active site of protomer A, the water accessibility of this protomer is diminished to 734 ± 60, 879 ± 71, 919 ± 63, and 880 ± 60 Å 2 for N3, 11a, 13b, and 14b, respectively. A reduction of water accessibility upon the binding of inhibitors to the enzyme active site is also found in the reported anti-HIV drugs, lopinavir and ritonavir, bound to the SARS-CoV-2 3CL pro [ 14 ] as well as in other protein-ligand complexations [ [53] , [54] , [55] ]. Since N3 is the largest molecule among studied inhibitors, accommodating well at the S1’ and S1-S5 sites, a lower water accessibility to the substrate-binding cleft is observed.…”

Enhanced Solubility and Anticancer Potential of Mansonone G By β-Cyclodextrin-Based Host-Guest Complexation: A Computational and Experimental Study

“…The inclusion complexes were generated in Accelrys Discovery Studio 2.5 (Accelrys Software Inc., San Diego, CA, USA) by docking protocols using CDOCKER module. The partial charges of MG molecule were created as per the standard procedures [33,34,35]. The Glycam-06 [36] and general AMBER force fields [37] were applied on βCDs and MG, respectively.…”