Crystal structures of porcine STINGCBD-CDN complexes reveal the mechanism of ligand recognition and discrimination of STING proteins
Crystal structures of porcine STINGCBD-CDN complexes reveal the mechanism of ligand recognition and discrimination of STING proteins
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猪STING(CBD)-CDN复合物的晶体结构揭示了STING蛋白的配体识别和区分机制
DOI：
10.1074/jbc.ra119.007367
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发表时间：
2019-07-26
影响因子：
4.8
通讯作者：
Gu, Lichuan
中科院分区：
文献类型：
--
作者：
Cong, Xiaoyan;Yuan, Zenglin;Gu, Lichuan
干扰素基因环二核苷酸刺激因子（cyclicdinucleotide，CDN-stimulatorofinterferongenes，STING）通路在动物病毒和细菌病原体的检测中起着重要作用。先前的研究已经表明，与细菌CDN如c-di-GMP、c-di-AMP和3 '，3'-cGAMP相比，由环状GMP-AMP合酶cGAS产生的后生动物第二信使环状[G（2 '，5'）pA（3 '，5'）p]（2 '，3'-cGAMP）以高亲和力结合STING。尽管最近的进展表明二聚STING的CDN结合结构域（CBD）优先于对称3 '，3'-CDN结合不对称2 '，3'-cGAMP，但STING分子（例如人STING）是否采用对称二聚体构象以有效地接合其不对称配体仍然是一个悬而未决的问题。在这里，来自猪STING（STING（CBD））的CBD与CDN复合的1.76-2.6埃分辨率的结构研究表明，猪STING（CBD）与其人类和小鼠对应物不同，可以采用不对称配体结合口袋来容纳CDN。我们观察到，不对称2 '，3'-cGAMP和配体结合口袋之间的广泛相互作用和形状互补性使其成为猪STING的最优选配体，并且几何约束限制了对称3 '，3'-CDN和猪STING之间的结合。这里观察到的猪STING的配体识别机制扩展了我们对CDN-STING途径如何被激活及其在抗病毒防御中的作用的理解。
The cyclic dinucleotide (CDN)-stimulator of interferon genes (STING) pathway plays an important role in the detection of viral and bacterial pathogens in animals. Previous studies have shown that the metazoan second messenger cyclic [G(2 ',5 ')pA(3 ',5 ')p] (2 ',3 '-cGAMP) generated by cyclic GMP-AMP synthase cGAS binds STING with high affinity compared with bacterial CDNs such as c-di-GMP, c-di-AMP, and 3 ',3 '-cGAMP. Despite recent progress indicating that the CDN-binding domain (CBD) of dimeric STING binds asymmetric 2 ',3 '-cGAMP preferentially over symmetric 3 ',3 '-CDNs, it remains an open question whether STING molecules, such as human STING, adopt a symmetric dimeric conformation to efficiently engage its asymmetric ligand. Here, structural studies of the CBD from porcine STING (STING(CBD)) in complex with CDNs at 1.76-2.6 angstrom resolution revealed that porcine STING(CBD), unlike its human and mouse counterparts, can adopt an asymmetric ligand-binding pocket to accommodate the CDNs. We observed that the extensive interactions and shape complementarity between asymmetric 2 ',3 '-cGAMP and the ligand-binding pocket make it the most preferred ligand for porcine STING and that geometry constraints limit the binding between symmetric 3 ',3 '-CDN and porcine STING. The ligand-discrimination mechanism of porcine STING observed here expands our understanding of how the CDN-STING pathway is activated and of its role in antiviral defense.