Structural Basis for the Activation of IKK1/α

Polley, Smarajit; Passos, Dario Oliveira; Huang, De-Bin; Mulero, María Carmen; Mazumder, Anup; Biswas, Tapan; Verma, Inder M.; Lyumkis, Dmitry; Ghosh, Gourisankar

doi:10.1016/j.celrep.2016.10.067

Cited by 47 publications

(47 citation statements)

References 34 publications

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“…IKKα and IKKβ are ubiquitously expressed serine/threonine kinases with 52% sequence identity and 70% homology [ 4 ]. They also share highly similar domain organisation and tertiary structure, as demonstrated by the recent X-ray crystal structures of human IKKα and IKKβ ( Figure 2 ; [ 5 , 6 , 7 ]. Activation of IKKα and IKKβ kinase activity requires the phosphorylation of specific residues in the activation loop of their active sites: serine-176 (S176) and serine-180 (S180) for IKKα and S177, and S181 for IKKβ [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 67%

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Prescott

Cook

2018

Cells

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Deregulated NF-κB signalling is implicated in the pathogenesis of numerous human inflammatory disorders and malignancies. Consequently, the NF-κB pathway has attracted attention as an attractive therapeutic target for drug discovery. As the primary, druggable mediator of canonical NF-κB signalling the IKKβ protein kinase has been the historical focus of drug development pipelines. Thousands of compounds with activity against IKKβ have been characterised, with many demonstrating promising efficacy in pre-clinical models of cancer and inflammatory disease. However, severe on-target toxicities and other safety concerns associated with systemic IKKβ inhibition have thus far prevented the clinical approval of any IKKβ inhibitors. This review will discuss the potential reasons for the lack of clinical success of IKKβ inhibitors to date, the challenges associated with their therapeutic use, realistic opportunities for their future utilisation, and the alternative strategies to inhibit NF-κB signalling that may overcome some of the limitations associated with IKKβ inhibition.

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Section: Introductionmentioning

confidence: 67%

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Prescott

Cook

2018

Cells

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“…Subsequent studies revealed that this complex composed canonically of IKKβ, IKKα, and NEMO can be reconstituted in vitro [28, 29]. Several crystal structures of nearly full-length IKKβ and a recent IKKα cryo-EM structure showed that these catalytic subunits exist primarily as dimers [30–32]. However, the oligomerization state of NEMO is controversial, and full-length NEMO has been observed to elute from SEC at a position that corresponds to a ~600 kDa globular protein [28].…”

Section: Characterization Of Nemo and The Ikk Holocomplexmentioning

confidence: 99%

Evidence for M1-Linked Polyubiquitin-Mediated Conformational Change in NEMO

Hauenstein

Kabaleeswaran

et al. 2017

Journal of Molecular Biology

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The NF-κB Essential Modulator (NEMO) is the scaffolding subunit of the inhibitor of κB kinase (IKK) holocomplex and is required for the activation of the catalytic IKK subunits, IKKα and IKKβ, during the canonical inflammatory response. Though structures of shorter constructs of NEMO have been solved, efforts to elucidate the full-length structure of NEMO have proven difficult due to its apparent high conformational plasticity. To better characterize the gross dimensions of full-length NEMO, we employed in-line size exclusion chromatography – small angle X-ray scattering (SEC-SAXS). We show that NEMO adopts a more compact conformation (Dmax=320 Å) than predicted for a fully extended coiled-coil structure (>500 Å). Additionally, we map a region of NEMO (residues 112-150) in its CC1 domain that impedes the binding of linear (M1-linked) di-ubiquitin to its CC2-LZ ubiquitin binding domain. This ubiquitin binding inhibition can be overcome by a longer chain of linear, but not K63-linked polyubiquitin. Collectively, these observations suggest that NEMO may be auto-inhibited in the resting state by intramolecular interactions, and that during signaling NEMO may be allosterically activated by binding to long M1-linked polyubiquitin chains.

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“…While the structures 5ebz, 5tqw, and 5tqx were determined by cryoEM, and their resolution was 5.60 Å, 5ebz.pdb was determined by X-ray crystallography, and its resolution was 4.50 Å. Therefore, 5ebz.pdb was selected for constructing the 3D structure in this study [ 21 ]. Its gene originated in Homo sapiens , and Spodoptera frugiperda was used as the expression system.…”

Section: Methodsmentioning

confidence: 99%

Chrysin Inhibits NF-κB-Dependent CCL5 Transcription by Targeting IκB Kinase in the Atopic Dermatitis-Like Inflammatory Microenvironment

Yeo

Lee

Koh

et al. 2020

IJMS

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Chrysin (5,7-dihydroxyflavone) is a natural polyphenolic compound that induces an anti-inflammatory response. In this study, we investigated the molecular mechanism underlying the chrysin-induced suppression of C-C motif chemokine ligand 5 (CCL5) gene expression in atopic dermatitis (AD)-like inflammatory microenvironment. We showed that chrysin inhibited CCL5 expression at the transcriptional level through the suppression of nuclear factor kappa B (NF-κB) in the inflammatory environment. Chrysin could bind to the ATP-binding pocket of the inhibitor of κB (IκB) kinase (IKK) and, subsequently, prevent IκB degradation and NF-κB activation. The clinical efficacy of chrysin in targeting IKK was evaluated in 2,4-dinitrochlorobenzene-induced skin lesions in BALB/c mice. Our results suggested that chrysin prevented CCL5 expression by targeting IKK to reduce the infiltration of mast cells to the inflammatory sites and at least partially attenuate the inflammatory responses. These findings suggested that chrysin might be useful as a platform for the design and synthesis of small-molecule IKK-targeting drugs for the treatment of chronic inflammatory diseases, such as AD.

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Structural Basis for the Activation of IKK1/α

Cited by 47 publications

References 34 publications

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Evidence for M1-Linked Polyubiquitin-Mediated Conformational Change in NEMO

Chrysin Inhibits NF-κB-Dependent CCL5 Transcription by Targeting IκB Kinase in the Atopic Dermatitis-Like Inflammatory Microenvironment

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