小柯机器人

德国波恩大学Matthias Geyer研究小组解析出与细胞因子释放抑制剂CRID3结合的NLRP3十聚体结构。2022年2月3日，《自然》杂志在线发表了这项成果。

Author: Hochheiser, Inga V., Pilsl, Michael, Hagelueken, Gregor, Moecking, Jonas, Marleaux, Michael, Brinkschulte, Rebecca, Latz, Eicke, Engel, Christoph, Geyer, Matthias

Issue&Volume: 2022-02-03

Abstract: NLRP3 is an intracellular sensor protein whose activation by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation and pyroptosis1,2. The conformational states of NLRP3 and the way antagonistic small molecules act at the molecular level remain poorly understood2,3. Here we report the cryo-electron microscopy structures of full-length human NLRP3 in its native form and complexed with the inhibitor CRID3 (also named MCC950)4. 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. Binding of CRID3 significantly stabilizes the NACHT and LRR domains relative to each other, allowing structural resolution of 3.8-4.2 . CRID3 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.

DOI: 10.1038/s41586-022-04467-w

Source: nature.com/articles/s41586-022-04467-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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