Biochemical and structural aspects of the ATP‐binding domain in inflammasome‐forming human NLRP proteins

MacDonald, Justin A.; Wijekoon, Champa; Liao, Kaihua; Muruve, Daniel A.

doi:10.1002/iub.1210

Cited by 67 publications

(72 citation statements)

References 67 publications

(141 reference statements)

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“…[20] N-Benzyl- Ethyl 3-(2-chlorophenyl)-2-(diethoxyphosphoryl)propanoate (20): 60 % NaH in mineral oil (1.64 g, 41.0 mmol) was added to a stirred solution of ethyl (diethoxyphosphoryl)acetate (7.86 g, 35.1 mmol) in DMF (30 mL) at 0 8C, and the mixture was stirred at 0 8C for 1 h. Then, 2-chlorophenylmethyl bromide (6.00 g, 29.3 mmol) was added at 0 8C, and the mixture was stirred at RT for 18 h. The reaction was quenched with water, and the mixture was extracted with EtOAc (50 mL 3). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried (Na 2 SO 4 ), and concentrated.…”

Section: -[(2-chlorophenyl)(hydroxy)methyl]-n-propylacrylamide (4)mentioning

confidence: 97%

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Design, Synthesis, and Evaluation of Acrylamide Derivatives as Direct NLRP3 Inflammasome Inhibitors

et al. 2016

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NLRP3 inflammasome plays a key role in the intracellular activation of caspase-1, processing of pro-inflammatory interleukin-1β (IL-1β), and pyroptotic cell death cascade. The overactivation of NLRP3 is implicated in the pathogenesis of autoinflammatory diseases, known as cryopyrin-associated periodic syndromes (CAPS), and in the progression of several diseases, such as atherosclerosis, type-2 diabetes, gout, and Alzheimer's disease. In this study, the synthesis of acrylamide derivatives and their pharmaco-toxicological evaluation as potential inhibitors of NLRP3-dependent events was undertaken. Five hits were identified and evaluated for their efficiency in inhibiting IL-1β release from different macrophage subtypes, including CAPS mutant macrophages. The most attractive hits were tested for their ability to inhibit NLRP3 ATPase activity on human recombinant NLRP3. This screening allowed the identification of 14, 2-(2-chlorobenzyl)-N-(4-sulfamoylphenethyl)acrylamide, which was able to concentration-dependently inhibit NLRP3 ATPase with an IC50 value of 74 μm. The putative binding pose of 14 in the ATPase domain of NLRP3 was also proposed.

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Section: -[(2-chlorophenyl)(hydroxy)methyl]-n-propylacrylamide (4)mentioning

confidence: 97%

“…[20] In fact, ATP hydrolysis is required to have active NLRP3 in the cytosol. [21] In a previous study, our group developed a series of electrophilic warheads preventing the NLRP3-dependent and ATPtriggered cell death of differentiated and primed THP-1 cells, which is a cellular model of macrophage pyroptosis.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Acrylamide Derivatives as Direct NLRP3 Inflammasome Inhibitors

et al. 2016

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“…This motif is thought to be involved in the coordination of a Mg 2þ ion, a crucial catalytic base for the ATPase activity of the NLR (Iyer et al, 2004;MacDonald et al, 2013). Impairment of ATPase activity in the tomato CC-NLR protein I-2 resulted in a constitutively active protein.…”

Section: Progress Towards a Mechanistic Understanding Of Plant Nlr Fumentioning

confidence: 99%

Animal NLRs provide structural insights into plant NLR function

Bentham

Burdett

Anderson

et al. 2016

Ann Bot

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Background The plant immune system employs intracellular NLRs (nucleotide binding [NB], leucine-rich repeat [LRR]/nucleotide-binding oligomerization domain [NOD]-like receptors) to detect effector proteins secreted into the plant cell by potential pathogens. Activated plant NLRs trigger a range of immune responses, collectively known as the hypersensitive response (HR), which culminates in death of the infected cell. Plant NLRs show structural and functional resemblance to animal NLRs involved in inflammatory and innate immune responses. Therefore, knowledge of the activation and regulation of animal NLRs can help us understand the mechanism of action of plant NLRs, and vice versa.Scope This review provides an overview of the innate immune pathways in plants and animals, focusing on the available structural and biochemical information available for both plant and animal NLRs. We highlight the gap in knowledge between the animal and plant systems, in particular the lack of structural information for plant NLRs, with crystal structures only available for the N-terminal domains of plant NLRs and an integrated decoy domain, in contrast to the more complete structures available for animal NLRs. We assess the similarities and differences between plant and animal NLRs, and use the structural information on the animal NLR pair NAIP/NLRC4 to derive a plausible model for plant NLR activation.Conclusions Signalling by cooperative assembly formation (SCAF) appears to operate in most innate immunity pathways, including plant and animal NLRs. Our proposed model of plant NLR activation includes three key steps: (1) initially, the NLR exists in an inactive auto-inhibited state; (2) a combination of binding by activating elicitor and ATP leads to a structural rearrangement of the NLR; and (3) signalling occurs through cooperative assembly of the resistosome. Further studies, structural and biochemical in particular, will be required to provide additional evidence for the different features of this model and shed light on the many existing variations, e.g. helper NLRs and NLRs containing integrated decoys.

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“…The recruitment of several caspase-1 molecules results in self-dimerization and perpetuated self-activation of caspase-1. The activated caspase-1 cleaves the prointerleukin (IL)-1b to generate the mature inflammatory cytokine ( Figure 2) [23].…”

Section: Inflammasomesmentioning

confidence: 99%