Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3
Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3
复制标题
DOI：
10.1038/s41586-022-04467-w
复制
发表时间：
2022-02-03
期刊：
影响因子：
64.8
通讯作者：
Geyer, Matthias
中科院分区：
文献类型：
--
作者：
Hochheiser, Inga, V;Pilsl, Michael;Geyer, Matthias
NLRP3是一种细胞内传感器蛋白，当受到广谱外源性和内源性刺激激活时，可导致炎性体形成和焦亡（1,2）。NLRP3的构象状态和拮抗小分子在分子水平上的作用方式仍然知之甚少（2,3）。在这里，我们报道了全长人NLRP3天然形态的低温电镜结构，并与抑制剂CRID3（也称为MCC950）络合(4)。非活性的adp结合NLRP3是一种十聚体，由交织在一起的富含亮氨酸重复序列（LRR）结构域的同型二聚体组成，它们作为五聚体背对背组装。NACHT结构域位于这个球形结构的顶轴。LRR笼内还形成一个吡啶结构域二聚体。两个相对的LRR结构域的凹位点之间的分子接触是由从LRR过渡段延伸的酸性环介导的。CRID3的结合大大稳定了NACHT和LRR结构域。CRID3结合成一个裂缝，将NACHT的四个子结构域与过渡LRR连接起来。它的中心磺脲基与NLRP3核苷酸结合域的Walker A基序相互作用，并夹在两个精氨酸残基之间，这解释了NLRP3对这种化学实体的特异性。随着这一关键治疗剂结合位点的确定，特异性靶向NLRP3治疗自身炎症和自身免疫性疾病，合理优化药物成为可能。
NLRP3 is an intracellular sensor protein that when activated by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation and pyroptosis(1,2). The conformational states of NLRP3 and the way antagonistic small molecules act at the molecular level remain poorly understood(2,3). 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.