Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3

吡喃结构域 NALP3 化学 二聚体 结合位点 血浆蛋白结合 立体化学 蛋白质结构 炎症体 测试表 结晶学 生物物理学 生物化学 生物 受体 有机化学
作者
Inga V. Hochheiser,Michael Pilsl,Gregor Hagelueken,Jonas Moecking,Michael Marleaux,Rebecca Brinkschulte,Eicke Latz,Christoph Engel,Matthias Geyer
出处
期刊:Nature [Nature Portfolio]
卷期号:604 (7904): 184-189 被引量:195
标识
DOI:10.1038/s41586-022-04467-w
摘要

NLRP3 is an intracellular sensor protein that when activated 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 leucine-rich repeat (LRR) domains that assemble back-to-back as pentamers. The NACHT domain is located at the apical axis of this spherical structure. One pyrin domain dimer is in addition formed inside the LRR cage. Molecular contacts between the concave sites of two opposing LRR domains are mediated by an acidic loop that extends from an LRR transition segment. Binding of CRID3 considerably stabilizes the NACHT and LRR domains relative to each other. 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 arginine residues, which explains the specificity of NLRP3 for this chemical entity. With the determination of the binding site of this key therapeutic agent, specific targeting of NLRP3 for the treatment of autoinflammatory and autoimmune diseases and rational drug optimization is within reach. Cryo-electron microscopy structures of human NLRP3 in its resting state and bound to the inhibitor CRID3 provide insight into the binding mechanism of CRID3 and its mode of antagonism.
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