Structure and Carbohydrate Recognition by the Nonmitogenic Lectin Horcolin

Abstract

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.

Synthesis and Antitubercular Evaluation of Diverse Glycosylated Ureas from D-Glucose

“…Mycobacterium tuberculosis resides in macrophages, the primary defense system of the host, and it was envisioned to synthesize some potential glycohybrid compounds which can penetrate the macrophages. Carbohydrates as earlier discussed have the potential for structural diversity [18][19][20][21][22][23][24][25] and have some crucial roles in the diverse biological process, notably hostpathogen interactions [26], signal transduction [27], and also infammations [28,29]. Because of the abovementioned reasons, we have synthesized substituted glycosyl ureas and their derivatives to see the structure-activity relationship (SAR) against M. tuberculosis and, at the same time, possessed in vitro activity as it would lead to a good candidate for the successful development of a mechanism-based new class of antituberculosis drug candidates.…”