Nature research paper: Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3
We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.NLRP3 is an intracellular sensor protein whose activation by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation and pyroptosis.
. Inactive, ADP-bound NLRP3 is a decamer composed of homodimers of intertwined LRR domains that assemble back-to-back as pentamers. The NACHT domain is located at the apical axis of this spherical structure. One PYD dimer is additionally formed inside the LRR cage. Molecular contacts between the concave sites of two opposing LRRs are mediated by an acidic loop extending from an LRR transition segment.
significantly stabilizes the NACHT and LRR domains relative to each other, allowing structural resolution of 3.8-4.2 Å. binds into a cleft, connecting four subdomains of the NACHT with the transition LRR. Its central sulfonylurea group interacts with the Walker A motif of the NLRP3 nucleotide-binding domain and is sandwiched between two arginines, explaining the specificity of NLRP3 for this chemical entity. With the determination of the binding site of this lead therapeutic, specific targeting of NLRP3 for the treatment of autoinflammatory and autoimmune diseases and rational drug optimization are within reach.
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