Conformational gating of dimannose binding to the antiviral protein cyanovirin revealed from the crystal structure at 1.35 Å resolution

Abstract

Cyanovirin (CV-N) is a small lectin with potent HIV neutralization activity, which could be exploited for a mucosal defense against HIV infection. The wild-type (wt) protein binds with high affinity to mannose-rich oligosaccharides on the surface of gp120 through two quasi-symmetric sites, located in domains A and B. We recently reported on a mutant of CV-N that contained a single functional mannose-binding site, domain B, showing that multivalent binding to oligomannosides is necessary for antiviral activity. The structure of the complex with dimannose determined at 1.8 Å resolution revealed a different conformation of the binding site than previously observed in the NMR structure of wt CV-N. Here, we present the 1.35 Å resolution structure of the complex, which traps three different binding conformations of the site and provides experimental support for a locking and gating mechanism in the nanoscale time regime observed by molecular dynamics simulations.

Structural insights into the specific anti-HIV property of actinohivin: structure of its complex with the α(1–2)mannobiose moiety of gp120

“…Several carbohydrate-binding proteins (lectins) have been isolated and characterized as candidates for suppressing gp120 binding to susceptible cells. Among them, cyanovirin-N (CV-N) has already been intensively investigated to determine its structural properties, carbohydrate-binding potential and antiviral activity (Bewley & Otero-Quintero, 2001;Bewley et al, 2002;Fromme et al, 2008;Tsai et al, 2004). Another lectin, griffithsin (GRFT), isolated from a red alga (Griffithsia sp.…”

Cyanobacterial lectins characteristics and their role as antiviral agents

“…Over the years, varied CV-N complexes with different carbohydrate structure have been analysed, with ligands such as dimannose Man␣1-2Man␣ [101], oligosaccharides such as hexamannoside or Man 9 GlcNAc 2 [86] and mutated CV-N with mannose dimmers [111]. Their studies suggested the involvement of two carbohydrate binding sites (primary and secondary) in CVN having varied affinity towards oligosaccharides [101].…”

The antiviral protein cyanovirin-N: the current state of its production and applications

“…Upon binding to gp120, Arg-76 undergoes a large conformational change, bringing its side chain from an unlocked position to a locked position, in which two direct hydrogen bonds to the ligand are formed. Glu-41 may contribute to the tight binding of the sugar and possibly in the selectivity for Manα(1-2)Manα (Fromme et al 2008). Recently, molecular-dynamics simulations in solution demonstrated no conformational preferences for Arg-76.…”