The intrinsic flexibility of IgE and its role in binding FcɛRI

Harwood, Naomi E.; McDonnell, James M.

doi:10.1016/j.biopha.2006.11.004

Cited by 12 publications

(11 citation statements)

References 34 publications

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“…In contrast to other immunoglobulin domains, the C3 domain was found to be in a molten globule conformation, holding a high degree of structural flexibility and adapting a well folded conformation upon binding to FcRI [60,61]. Previous studies on the FcRI-IgE interaction have revealed conformational changes upon binding in the IgE molecule, preventing binding of additional FcRI␣ molecules [60,61]. In fact, in our competition assays, the DARPins were able to interfere with the binding of IgE to FcRI (Figs.…”

Section: Discussionmentioning

confidence: 87%

DARPins against a functional IgE epitope

et al. 2010

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Section: Discussionmentioning

confidence: 87%

DARPins against a functional IgE epitope

et al. 2010

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“…Besides being an intermediate in protein folding, the molten globule state, with its increased structural flexibility, can also have biological functions. There are examples of molten globules that have an important role in the insertion of proteins into membranes and in binding of DNA or receptor molecules [63–65]. We cannot state whether CyrA exists as a molten globule state in vivo and has a particular function, or whether the molten globule is only observed as an in vitro folding intermediate.…”

Section: Discussionmentioning

confidence: 99%

A novel prokaryotic l‐arginine:glycine amidinotransferase is involved in cylindrospermopsin biosynthesis

et al. 2010

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We report the first characterization of an l‐arginine:glycine amidinotransferase from a prokaryote. The enzyme, CyrA, is involved in the pathway for biosynthesis of the polyketide‐derived hepatotoxin cylindrospermopsin from Cylindrospermopsis raciborskii AWT205. CyrA is phylogenetically distinct from other amidinotransferases, and structural alignment shows differences between the active site residues of CyrA and the well‐characterized human l‐arginine:glycine amidinotransferase (AGAT). Overexpression of recombinant CyrA in Escherichia coli enabled biochemical characterization of the enzyme, and we confirmed the predicted function of CyrA as an l‐arginine:glycine amidinotransferase by 1H NMR. As compared with AGAT, CyrA showed narrow substrate specificity when presented with substrate analogs, and deviated from regular Michaelis–Menten kinetics in the presence of the non‐natural substrate hydroxylamine. Studies of initial reaction velocities and product inhibition, and identification of intermediate reaction products, were used to probe the kinetic mechanism of CyrA, which is best described as a hybrid of ping‐pong and sequential mechanisms. Differences in the active site residues of CyrA and AGAT are discussed in relation to the different properties of both enzymes. The enzyme had maximum activity and maximum stability at pH 8.5 and 6.5, respectively, and an optimum temperature of 32 °C. Investigations into the stability of the enzyme revealed that an inactivated form of this enzyme retained an appreciable amount of secondary structure elements even on heating to 94 °C, but lost its tertiary structure at low temperature (Tmax of 44.5 °C), resulting in a state reminiscent of a molten globule. CyrA represents a novel group of prokaryotic amidinotransferases that utilize arginine and glycine as substrates with a complex kinetic mechanism and substrate specificity that differs from that of the eukaryotic l‐arginine:glycine amidinotransferases.

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“…Small molecule inhibitors of the binding reaction work well in slowing the forward binding reaction, but because the affinity of IgE for FcεRI is so high (dissociation half-life of 5–10 days), most small molecule inhibitors don’t ultimately reduce cell-bound IgE sufficiently to suppress allergen-mediated secretion (although refinements of this approach are still underway, [65, 66]). The studies with omalizumab define the requirements quite well; cell-surface suppression must be on the order of 99% [67].…”

Section: The Root Of the Problemmentioning

confidence: 99%

IgE-dependent signaling as a therapeutic target for allergies

MacGlashan¹

2012

Trends in Pharmacological Sciences

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Atopic diseases are complex, with many immunological participants, but the central element in their expression is IgE antibody. In an atopic individual, the immune system pathologically reacts to environmental substances by producing IgE, and these allergen-specific IgE antibodies confer to IgE receptor-bearing cells responsiveness to the environmental substances. Mast cells and basophils are central to the immediate hypersensitivity reaction that is mediated by IgE. In humans, there are various other immune cells, notably dendritic cells and B cells, which can also bind IgE. For mast cells, basophils and dendritic cells, the receptor that binds IgE is the high affinity receptor, FcεRI. For B cells and a few other cell types, the low affinity receptor, FcεRII, provides the cell a means to sense the presence of IgE. This overview will focus on events following activation of the high-affinity receptor because FcεRI generates the classical immediate hypersensitivity reaction.

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The intrinsic flexibility of IgE and its role in binding FcɛRI

Cited by 12 publications

References 34 publications

DARPins against a functional IgE epitope

DARPins against a functional IgE epitope

A novel prokaryotic l‐arginine:glycine amidinotransferase is involved in cylindrospermopsin biosynthesis

IgE-dependent signaling as a therapeutic target for allergies

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