Predicting and validating a model of suppressor of IKKepsilon through biophysical characterization

Machek, Megan L.; Sonnenschein, Halie A.; Graham, Sasha‐Kaye I.; Shikwana, Flowreen; Kim, Seung‐Hwan L.; DuBar, Selena Garcia; Minzer, Ian D.; Wey, Ryan; Bell, Jessica K.

doi:10.1002/pro.3640

Cited by 2 publications

(2 citation statements)

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“…SIKE was initially identified as an IKKε-associated protein through yeast two-hybrid screening, and it is ubiquitously expressed in various tissues [ 29 , 30 ]. The profound involvement of IKKε in inflammation and immunity demonstrates the potential of SIKE in regulating the progression of immune diseases [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

“…Suppressor of IKKε (SIKE), as a small coiled-coil domain-containing protein comprised of 207 amino-acid residues, is widely expressed in most tissues, such as the heart, stomach and kidney [ 29 ]. SIKE has been identified as an interaction partner for IKKε and a negative modulator of the interferon pathway through negatively regulating TBK1-involved signaling [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Nrf2 mitigates prolonged PM2.5 exposure-triggered liver inflammation by positively regulating SIKE activity: Protection by Juglanin

Ge¹,

Tan

Zhong

et al. 2020

Redox Biology

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Air pollution containing particulate matter (PM) less than 2.5 μm (PM 2.5 ) plays an essential role in regulating hepatic disease. However, its molecular mechanism is not yet clear, lacking effective therapeutic strategies. In this study, we attempted to investigate the effects and mechanisms of PM 2.5 exposure on hepatic injury by the in vitro and in vivo experiments. At first, we found that PM 2.5 incubation led to a significant reduction of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), along with markedly reduced expression of different anti-oxidants. Notably, suppressor of IKKε (SIKE), known as a negative regulator of the interferon pathway, was decreased in PM 2.5 -incubated cells, accompanied with increased activation of TANK-binding kinase 1 (TBK1) and nuclear factor-κB (NF-κB). The in vitro studies showed that Nrf2 positively regulated SIKE expression under the conditions with or without PM 2.5 . After PM 2.5 treatment, Nrf2 knockdown further accelerated SIEK decrease and TBK1/NF-κB activation, and opposite results were observed in cells with Nrf2 over-expression. Subsequently, the gene loss- and gain-function analysis demonstrated that SIKE deficiency further aggravated inflammation and TBK1/NF-κB activation caused by PM 2.5 , which could be abrogated by SIKE over-expression. Importantly, SIKE-alleviated inflammation was mainly dependent on TBK1 activation. The in vivo studies confirmed that SIKE- and Nrf2-knockout mice showed significantly accelerated hepatic injury after long-term PM 2.5 exposure through reducing inflammatory response and oxidative stress. Juglanin (Jug), mainly isolated from Polygonum aviculare , exhibits anti-inflammatory and anti-oxidant effects. We found that Jug could increase Nrf2 activation, and then up-regulated SIKE in cells and liver tissues, mitigating PM 2.5 -induced liver injury. Together, all these data demonstrated that Nrf2 might positively meditate SIKE to inhibit inflammatory and oxidative damage, ameliorating PM 2.5 -induced liver injury. Jug could be considered as an effective therapeutic strategy against this disease by improving Nrf2/SIKE signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nrf2 mitigates prolonged PM2.5 exposure-triggered liver inflammation by positively regulating SIKE activity: Protection by Juglanin

Ge¹,

Tan

Zhong

et al. 2020

Redox Biology

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Allosterism and Drug Discovery

Bell

2021

Burger's Medicinal Chemistry and Drug Discovery

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Interest in allostery and drug development has significantly expanded with increasingly broad ranges of targets and diseases. Experimental and computational approaches have led to advances in understanding of the mechanisms and roles of protein dynamics and conformational states, and come together in the concept of conformational selection. The models of Monod, Wyman, and Changeux and Koshland, Nemethy, and Filmer provide conceptual explanations of homotropic cooperativity and heterotropic allostery, while conformational selection provides realistic detail that can be exploited in drug design. Distinction between allostery and cooperativity and development of approaches to identify cryptic sites on proteins significantly expands the range of targets for allosteric drug design. High‐throughput screening and SAR optimization remain a staple of drug design, however, increased understanding of the thermodynamics of protein–ligand interactions and conformational changes, and the mechanisms of information flow between existing allosteric sites and across subunit interfaces or between allosteric and active sites, rational design of ligands to interact with a cryptic “allosteric” site on any protein becomes possible. Recent “omics” approaches to identify druggable targets both genome wide and in vivo further enhance the range of targets for drug design, both covalent and noncovalent, exploiting allosteric and cooperative properties of proteins.

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Predicting and validating a model of suppressor of IKKepsilon through biophysical characterization

Cited by 2 publications

References 49 publications

Nrf2 mitigates prolonged PM2.5 exposure-triggered liver inflammation by positively regulating SIKE activity: Protection by Juglanin

Nrf2 mitigates prolonged PM2.5 exposure-triggered liver inflammation by positively regulating SIKE activity: Protection by Juglanin

Allosterism and Drug Discovery

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