Distinct Dynamic and Conformational Features of Human STING in Response to 2′3′-cGAMP and c-di-GMP

Jingjing Guo, Jie Wang, Jingrong Fan, Yan Zhang, Wenpei Dong, Chang Po Chen

研究成果: Article同行評審

9 引文 斯高帕斯(Scopus)

摘要

The human stimulator of interferon genes protein (hSTING) can bind cyclic dinucleotides (CDNs) to activate the production of type I interferons and inflammatory cytokines. These CDNs can be either bacterial secondary messengers, 3′3′-CDNs, or endogenous 2′3′-cGAMP. cGAMP, with a unique 2′–5′ bond, is the most potent activator of hSTING among all CDNs. However, current understanding of the molecular principles underlying the unique ability of 2′3′-cGAMP to potently activate hSTINGs other than 3′3′-CDNs remains incomplete. In this work, molecular dynamics simulations were used to provide an atomistic picture of the binding of 2′3′-cGAMP and one 3′3′-CDN (c-di-GMP) to hSTING. The results suggest that hSTING binds more strongly to 2′3′-cGAMP than to c-di-GMP, which prefers to bind with a more open and flexible state of hSTING. Finally, a potential “dock–lock–anchor” mechanism is proposed for the activation of hSTING upon the binding of a potent ligand. It is believed that deep insights into understanding the binding of hSTING with 3′3′-CDNs and the endogenous 2′3′-cGAMP would help to establish the principles underlying powerful 2′3′-cGAMP signaling and the nature of hSTING activation, as well as related drug design.

原文English
頁(從 - 到)1838-1847
頁數10
期刊ChemBioChem
20
發行號14
DOIs
出版狀態Published - 15 7月 2019
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