Lectins as HIV Microbicides

Koharudin, Leonardus M. I.; Gronenborn, Angela M.

doi:10.1007/978-1-4614-8872-9_7

Cited by 4 publications

(4 citation statements)

References 91 publications

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“…60−62 Different multimeric domainswapped structures have been observed for cyanovirin-N, suggesting trapped folding intermediates. 63 For cyt c, a transient dimer has been detected by SAXS measurements during refolding. 54 We have demonstrated that domain-swapped oligomers of cyt c are formed during folding from its guanidinium ion-induced denatured state by intermolecular hydrophobic interaction between the N-and C-terminal αhelices.…”

Section: ■ Discussionmentioning

confidence: 99%

Formation of Domain-Swapped Oligomer of Cytochrome c from Its Molten Globule State Oligomer

et al. 2014

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Many proteins, including cytochrome c (cyt c), have been shown to form domain-swapped oligomers, but the factors governing the oligomerization process remain unrevealed. We obtained oligomers of cyt c by refolding cyt c from its acid molten globule state to neutral pH state under high protein and ion concentrations. The amount of oligomeric cyt c obtained depended on the nature of the anion (chaotropic or kosmotropic) in the solution: ClO4(-) (oligomers, 11% ± 2% (heme unit)), SCN(-) (10% ± 2%), I(-) (6% ± 2%), NO3(-) (3% ± 1%), Br(-) (2% ± 1%), Cl(-) (2% ± 1%), and SO4(2-) (3% ± 1%) for refolding of 2 mM cyt c (anion concentration 125 mM). Dimeric cyt c obtained by refolding from the molten globule state exhibited a domain-swapped structure, in which the C-terminal α-helices were exchanged between protomers. According to small-angle X-ray scattering measurements, approximately 25% of the cyt c molecules were dimerized in the molten globule state containing 125 mM ClO4(-). These results indicate that a certain amount of molten globule state oligomers of cyt c convert to domain-swapped oligomers during refolding and that the intermolecular interactions necessary for domain swapping are present in the molten globule state.

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Section: ■ Discussionmentioning

confidence: 99%

Formation of Domain-Swapped Oligomer of Cytochrome c from Its Molten Globule State Oligomer

et al. 2014

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“…27 It has been suggested that domain-swapped oligomers of cyanovirin-N are trapped folding intermediates. 28 The heme of horse myoglobin has been shown to dissociate from the protein during formation of its domainswapped dimer, presumably because of a protein structural change at the active site. 29 Although the formation of domainswapped oligomers during folding may be a common character of many proteins, the detailed mechanism and interaction responsible for oligomerization remain unknown.…”

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confidence: 99%

Formation of Oligomeric Cytochrome c during Folding by Intermolecular Hydrophobic Interaction between N- and C-Terminal α-Helices

et al. 2013

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We have previously shown that horse cytochrome c (cyt c) forms oligomers by domain swapping its C-terminal α-helix when interacting with ethanol. Although folding of cyt c has been studied extensively, formation of domain-swapped oligomers of cyt c during folding has never been reported. We found that domain-swapped oligomeric cyt c is produced during refolding from its guanidinium ion-induced unfolded state at high protein concentrations and low temperatures. The obtained dimer exhibited a domain-swapped structure exchanging the C-terminal α-helical region between molecules. The extent of dimer formation decreased significantly for the folding of C-terminal cyt c mutants with reduced hydrophobicity achieved by replacement of hydrophobic residues with Gly in the C-terminal region, whereas a large amount of heterodimers was generated for the folding of a mixture of N- and C-terminal mutants. These results show that cyt c oligomers are formed through intermolecular hydrophobic interaction between the N- and C-terminal α-helices during folding. A slow phase (4-5 s) was observed in addition to a 400-500 ms phase during folding of a high concentration of cyt c in the presence of 1.17 M guanidine hydrochloride. The fast phase is attributed to the intramolecular ligand exchange process, and we attribute the slow phase to the ligand exchange process in oligomers. These results show that it is important to consider formation of domain-swapped oligomeric proteins when folding at high protein concentrations.

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“…Cyanovirin-N (CV-N) is a small (11-kDa) lectin isolated from the cyanobacterium Nostoc ellipsosporum , which possesses antiviral activity against HIV and other enveloped viruses, such as Ebola and influenza ( Barrientos and Gronenborn 2005 ; Koharudin and Gronenborn 2014 ). Its anti-HIV activity is mediated through binding to high mannose glycans (such as Man-9; Figure 1A ) decorating the envelope glycoprotein gp120.…”

Section: Introductionmentioning

confidence: 99%

A detailed picture of a protein–carbohydrate hydrogen-bonding network revealed by NMR and MD simulations

et al. 2020

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Cyanovirin-N (CV-N) is a cyanobacterial lectin with antiviral activity towards HIV and several other viruses. Here, we identify mannoside hydroxyl protons that are hydrogen bonded to the protein backbone of the CV-N domain B binding site, using NMR spectroscopy. For the two carbohydrate ligands Manα(1 → 2)ManαOMe and Manα(1 → 2) Manα(1 → 6)ManαOMe five hydroxyl protons, each, are involved in hydrogen-bonding networks. Comparison with previous crystallographic results revealed that four of these hydroxyl protons donate hydrogen bonds to protein backbone carbonyl oxygens in solution and in the crystal. Hydrogen bonds were not detected between the side chains of Glu41 and Arg76 with sugar hydroxyls, as previously proposed for CV-N binding of mannosides. Molecular dynamics simulations of the CV-N/Manα(1 → 2)Manα(1 → 6)ManαOMe complex confirmed the NMR-determined hydrogen-bonding network. Detailed characterization of CV-N/mannoside complexes provides a better understanding of lectin-carbohydrate interactions and opens up to the use of CV-N and similar lectins as antiviral agents.

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Lectins as HIV Microbicides

Cited by 4 publications

References 91 publications

Formation of Domain-Swapped Oligomer of Cytochrome c from Its Molten Globule State Oligomer

Formation of Domain-Swapped Oligomer of Cytochrome c from Its Molten Globule State Oligomer

Formation of Oligomeric Cytochrome c during Folding by Intermolecular Hydrophobic Interaction between N- and C-Terminal α-Helices

A detailed picture of a protein–carbohydrate hydrogen-bonding network revealed by NMR and MD simulations

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