A simple model for determining affinity from irreversible thermal shifts

Hall, J. Perry

doi:10.1002/pro.3701

Cited by 18 publications

(12 citation statements)

References 20 publications

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“…The ΔG of ligand binding results in a change in melting temperature of the The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism target protein (ΔT m ). This thermal shift thus provides a convenient, if indirect method of comparing binding affinities (33), as evidenced by the ∼20°C increase in T m observed for Bla g 1 when bound to its nMix natural ligands or their saturated equivalents (16:0 to 18:0) (17). Binding of nMix ligands did not significantly perturb the overall alpha-helical content of AEG12 when assessed using circular dichroism (SI Appendix, Fig.…”

Section: Aeg12-mediated Delivery Of Unsaturated Fatty Acids Destabilizesmentioning

confidence: 99%

The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism

Foo

Thompson

Chen

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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The mosquito protein AEG12 is up-regulated in response to blood meals and flavivirus infection though its function remained elusive. Here, we determine the three-dimensional structure of AEG12 and describe the binding specificity of acyl-chain ligands within its large central hydrophobic cavity. We show that AEG12 displays hemolytic and cytolytic activity by selectively delivering unsaturated fatty acid cargoes into phosphatidylcholine-rich lipid bilayers. This property of AEG12 also enables it to inhibit replication of enveloped viruses such as Dengue and Zika viruses at low micromolar concentrations. Weaker inhibition was observed against more distantly related coronaviruses and lentivirus, while no inhibition was observed against the nonenveloped virus adeno-associated virus. Together, our results uncover the mechanistic understanding of AEG12 function and provide the necessary implications for its use as a broad-spectrum therapeutic against cellular and viral targets.

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Section: Aeg12-mediated Delivery Of Unsaturated Fatty Acids Destabilizesmentioning

confidence: 99%

The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism

Foo

Thompson

Chen

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…While the ΔG of ligand binding generally enhances the thermodynamic stability of the resulting complex ( 126 ), key exceptions exist. One illustrative example can be found among plant Lipid Transfer Proteins (LTP).…”

Section: Lipid Ligands As Modulators Of Abundance and Stabilitymentioning

confidence: 99%

Abundance and Stability as Common Properties of Allergens

Foo¹,

Mueller²

2021

Front. Allergy

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There have been many attempts to identify common biophysical properties which differentiate allergens from their non-immunogenic counterparts. This review will focus on recent studies which examine two such factors: abundance and stability. Anecdotal accounts have speculated that the elevated abundance of potential allergens would increase the likelihood of human exposure and thus the probability of sensitization. Similarly, the stability of potential allergens dictates its ability to remain a viable immunogen during the transfer from the source to humans. This stability could also increase the resilience of potential allergens to both gastric and endosomal degradation, further skewing the immune system toward allergy. Statistical analyses confirm both abundance and stability as common properties of allergens, while epidemiological surveys show a correlation between exposure levels (abundance) and allergic disease. Additional studies show that changes in protein stability can predictably alter gastric/endosomal processing and immunogenicity, providing a mechanistic link between stability and allergenicity. However, notable exceptions exist to both hypotheses which highlight the multifaceted nature of immunological sensitization, and further inform our understanding of some of these other factors and their contribution to allergic disease.

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“…1) [6,7]. While the unique nature of the AEG12–ligand complex precludes traditional equilibrium‐based K D measurements, the large thermal shift observed upon ligand binding is consistent with the formation of a stable, high‐affinity complex that is potentially amenable for therapeutic use [6,7,26].…”

Section: Resultsmentioning

confidence: 99%

Expanding the antiviral potential of the mosquito lipid‐transfer protein AEG12 against SARS‐CoV‐2 using hydrophobic antiviral ligands

2022

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The mosquito protein AEG12 encompasses a large (~3800 Å3 ) hydrophobic cavity which binds and delivers unsaturated fatty acids into biological membranes, allowing it to lyse cells and neutralize a wide range of enveloped viruses. Herein, the lytic and antiviral activities are modified with nonnaturally occurring lipid ligands. We generated novel AEG12 complexes in which the endogenous fatty acid ligands were replaced with hydrophobic viral inhibitors. The resulting compounds modulated cytotoxicity and infectivity against SARS-CoV-2, potentially reflecting additional mechanisms of action beyond membrane destabilization. These studies provide valuable insight into the design of novel broad-spectrum antiviral therapeutics centred on the AEG12 protein scaffold as a delivery vehicle for hydrophobic therapeutic compounds.

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A simple model for determining affinity from irreversible thermal shifts

Cited by 18 publications

References 20 publications

The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism

The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism

Abundance and Stability as Common Properties of Allergens

Expanding the antiviral potential of the mosquito lipid‐transfer protein AEG12 against SARS‐CoV‐2 using hydrophobic antiviral ligands

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