Glycosylation constitutes one of the most common, ubiquitous and complex forms of post-translational modification. It commences with the synthesis of the protein and plays a significant role in deciding its folded state, oligomerization and thus its function. Recent studies have demonstrated that N-linked glycans help proteins to fold as the stability and folding kinetics are altered with the removal of the glycans from them. Several studies have shown that it alters not only the thermodynamic stability but also the structural features of the folded proteins modulating their interactions and functions. Their inhibition and perturbations have been implicated in diseases from diabetes to degenerative disorders. The intent of this review is to provide insight into the recent advancements in the general understanding on the aspect of glycosylation driven stability of proteins that is imperative to their function and finally their role in health and disease states.
The SARS-CoV-2 virus has been known to gain entry into the host cell through the spike protein that binds to the host ACE2 cell surface protein. However, the role of the putative sugar-binding sites in the spike protein has remained unclear. We provide a comprehensive in silico outlook into the infection initiation wherein the virus first recognizes the sialosides on the cell via its S1A domain of the spike protein as it surfs over the cell surface. This facilitates the subsequent interaction with the cellular glycosaminoglycans through the S1B domain of the spike protein as it binds to the ACE2 receptor. The unique coadaptation to recognize both the host protein and the cell-surface carbohydrate receptors provides an additional coupling mechanism for efficient viral attachment and infection.
In our recent studies on prevalence of multidrug resistant pathogens in Byramangala reservoir, Karnataka, India, we identified Salmonella typhi, Staphylococcus aureus, and Vibrio cholerae which had acquired multiple drug resistance (MDR) and emerged as superbugs. Hence, there is a pressing demand to identify alternative therapeutic remedies. Our study focused on the screening of herbal leads by structure-based virtual screening. The virulent gene products of these pathogens towards Kanamycin(aph), Trimethoprim(dfrA1), Methicillin (mecI), and Vancomycin (vanH) were identified as the probable drug targets and their 3D structures were predicted by homology modeling. The predicted models showed good stereochemical validity. By extensive literature survey, we selected 58 phytoligands and their drug likeliness and pharmacokinetic properties were computationally predicted. The inhibitory properties of these ligands against drug targets were studied by molecular docking. Our studies revealed that Baicalein from S. baicalensis (baikal skullcap) and Luteolin from Taraxacum officinale (dandelion) were identified as potential inhibitors against aph of S. typhi. Resveratrol from Vitis vinifera (grape vine) and Wogonin from S. baicalensis were identified as potential inhibitors against dfrA1 of S. typhi. Herniarin from Herniaria glabra (rupture worts) and Pyrocide from Daucus carota (Carrot) were identified as the best leads against dfrA1 of V. cholerae. Taraxacin of T. officinale (weber) and Luteolin were identified as potential inhibitors against Mec1. Apigenin from Coffee arabica (coffee) and Luteolin were identified as the best leads against vanH of S. aureus. Our findings pave crucial insights for exploring alternative therapeutics against MDR pathogens.
Lectins are sugar-binding proteins that have shown considerable promise as antiviral agents because of their ability to interact with envelope glycoproteins present on the surface of viruses such as HIV-1. However, their therapeutic potential has been compromised by their mitogenicity that stimulates uncontrolled division of Tlymphocytes. Horcolin, a member of the jacalin family of lectins, tightly binds the HIV-1 envelope glycoprotein gp120 and neutralizes HIV-1 particles but is nonmitogenic. In this report, we combine X-ray crystallography and NMR spectroscopy to obtain atomic-resolution insights into the structure of horcolin and the molecular basis for its carbohydrate recognition. Each protomer of the horcolin dimer adopts a canonical β-prism I fold with three Greek key motifs and carries two carbohydrate-binding sites. The carbohydrate molecule binds in a negatively charged pocket and is stabilized by backbone and side chain hydrogen bonds to conserved residues in the ligand-binding loop. NMR titrations reveal a two-site binding mode and equilibrium dissociation constants for the two binding sites determined from two-dimensional (2D) lineshape modeling are 4-fold different. Single-binding-site variants of horcolin confirm the dichotomy in binding sites and suggest that there is allosteric communication between the two sites. An analysis of the horcolin structure shows a network of hydrogen bonds linking the two carbohydrate-binding sites directly and through a secondary binding site, and this coupling between the two sites is expected to assume importance in the interaction of horcolin with high-mannose glycans found on viral envelope glycoproteins.
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