苏拉明及其类似物是cGAS的多功能抑制剂。

Abstract

Suramin and its analogues inhibit the catalytic activity of human and mouse cGAS. • cGAS binds the suramin analogue NF023, forming 1:1 and 2:3 complexes. • NF023 prevents substrate access to the active site and blocks cGAS-DNA binding. • Suramin and NF023 disrupt cGAS-DNA phase separation. Upon sensing double-stranded DNA, cyclic GMP-AMP synthase (cGAS) catalyzes ATP and GTP to synthesize the cyclic dinucleotide 2′,3′-cGAMP, which subsequently activates stimulator of interferon genes (STING)-mediated immune responses. Modulation of cGAS catalytic activity is crucial for treating diseases associated with the cGAS-STING pathway. Here, we found that suramin and its analogues, such as NF023, can inhibit 2′,3′-cGAMP synthesis by competitively binding to cGAS. Structural analysis of the cGAS-NF023 complex reveals that NF023 binds to the active-site cleft and DNA-binding sites of cGAS, which prevents substrate access to the active site, stabilizes the activation loop in an inactive conformation and blocks cGAS-DNA binding. In addition, both suramin and NF023 disrupt cGAS-DNA phase separation, thereby potentially impairing cytosolic DNA sensing and downstream signal transduction. These findings unveil the unique mechanisms underlying cGAS inhibition by suramin and its analogues and provide the structural basis for developing cGAS inhibitors. Download: Download high-res image (206KB) Download: Download full-size image