Sampling of Glycan‐Bound Conformers by the Anti‐HIV Lectin Oscillatoria agardhii agglutinin in the Absence of Sugar

Abstract

Lectins from different sources have been shown to interfere with HIV infection by binding to the sugars of viral envelope glycoproteins. Three-dimensional atomic structures of a number of HIV-inactivating lectins have been determined, both as free proteins and in glycan-bound forms. However, details on the mechanism of recognition and binding to sugars are elusive. Here we focus on the anti-HIV lectin from Oscillatoria agardhii (OAA): we show that in the absence of sugar in solution, both sugar-free and sugar-bound protein conformations that were observed in the X-ray structures exist as conformational sub-states. Our results suggest that glycan recognition occurs via conformational selection within the ground state, differing from the popular “excited” state model. Our findings provide further insight into molecular recognition of the major receptor on the HIV virus by OAA, details which can potentially be used for optimization and/or development of preventive anti-HIV therapeutics.

Antiviral lectins: Selective inhibitors of viral entry

“…The crystal structures of OAAH are each comprised of 10 β-strands that fold into a β-barrel-like architecture with the mannose binding sites localized to the loops between β1- β2 and β9- β10 for CRD1 and β4- β5 and β6- β7 for CRD2 and NMR solution structures in bound and free state revealed dynamic loops at the CRD ( Carneiro et al, 2015 , Koharudin et al., 2011 ). The CRDs of Oscillatoria agardhii Agglutinin Homologes (OAAH) antiviral lectins have consensus sequences that include three regions specifically defined as (using OAA numbering) residues 7–11 (NQWGG), 93–99 (GXRX (1,2) QXV), and 122–128 (GEGPIGF).…”

Cyanobacterial lectins characteristics and their role as antiviral agents

“…OAA and rOAA exhibits specificity towards high-mannose N-glycans (1 and 4) bearing nonreducing terminal (␣1-3) mannose in the D2 arm and also requires the reducing terminal GlcNAc residue(s) for its binding [56,80]. OAA exhibits unique specificity towards ␣-3,␣-6-mannopentaose (1)(2)(3)(4)(5)(6)]Man␣(1-6)Man)) which is branched core unit of Man-9 [50,57,98]. O. agardii agglutinin homolog (OAAH) also exhibits specificity towards ␣-3,␣-6-mannopentaose [99].…”

“…Solution structure analysis of OAA also reveals a ␤-barrel fold consisting of 10 antiparallel ␤-strands [98]. In solution, protein conformations (sugar-free and sugar-bound) coexist in equilibrium and glycan recognition occurs by conformational selection from ground state ensemble owing to abundantly present boundconformation [98].…”

“…In solution, protein conformations (sugar-free and sugar-bound) coexist in equilibrium and glycan recognition occurs by conformational selection from ground state ensemble owing to abundantly present boundconformation [98]. Data survey from various internet sources.…”

Lectins engineered to favor a glycan-binding conformation have enhanced antiviral activity

“…The OAA protein slightly changes its conformation upon binding to glycan (31,32). Such conformational change has been proposed to be due to a "population shift" mechanism rather than to the common "induced fit" mechanism (34).…”