Structure-Function Analysis of STING Activation by c[G(2 %26apos;,5 %26apos;) pA(3 %26apos;,5 %26apos;)p] and Targeting by Antiviral DMXAA

作者：Gao Pu; Ascano Manuel; Zillinger Thomas; Wang Weiyi; Dai Peihong; Serganov Artem A; Gaffney Barbara L; Shuman Stewart; Jones Roger A; Deng Liang; Hartmann Gunther; Barchet Winfried^*; Tuschl Thomas; Patel Dinshaw J

来源：Cell, 2013, 154(4): 748-762.

DOI：10.1016/j.cell.2013.07.023

Binding of dsDNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) triggers formation of the metazoan second messenger c[G(2%26apos;,5%26apos;)pA(3%26apos;,5%26apos;)p], which binds the signaling protein STING with subsequent activation of the interferon (IFN) pathway. We show that human hSTING H232 adopts a %26quot;closed%26quot; conformation upon binding c[G(2%26apos;,5%26apos;) pA(3%26apos;,5%26apos;) p] and its linkage isomer c[G(2%26apos;,5%26apos;) pA(2%26apos;,5%26apos;) p], as does mouse mSting(R231) on binding c[G(2%26apos;,5%26apos;) pA(3%26apos;,5%26apos;) p], c[G(3%26apos;,5%26apos;) pA(3%26apos;,5%26apos;) p] and the antiviral agent DMXAA, leading to similar %26quot;closed%26quot; conformations. Comparing hSTING to mSting, 2%26apos;,5%26apos;-linkage-containing cGAMP isomers were more specific triggers of the IFN pathway compared to the all-3%26apos;,5%26apos;-linkage isomer. Guided by structural information, we identified a unique point mutation (S162A) placed within the cyclic-dinucleotide-binding site of hSTING that rendered it sensitive to the otherwise mouse-specific drug DMXAA, a conclusion validated by binding studies. Our structural and functional analysis highlights the unexpected versatility of STING in the recognition of natural and synthetic ligands within a small-molecule pocket created by the dimerization of STING.

• 出版日期2013-8-15
• 单位rutgers