Structural basis of coronavirus E protein interactions with human PALS1 PDZ domain.
Structural basis of coronavirus E protein interactions with human PALS1 PDZ domain.
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DOI：
10.1038/s42003-021-02250-7
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发表时间：
2021-06-11
影响因子：
5.9
通讯作者：
Kvansakul M
中科院分区：
文献类型：
--
作者：
Javorsky A;Humbert PO;Kvansakul M
感染SARS-CoV-2会导致2019年冠状病毒病(新冠肺炎)，与严重和危及生命的肺炎和呼吸衰竭有关。然而，这些症状的分子基础仍不清楚。SARS-CoV-1E蛋白通过与CRumbs极性复合体的关键成分PALS1 PDZ结构域结合，干扰了人上皮细胞对细胞极性和细胞-细胞连接完整性的控制。我们发现SARS-CoV-1和SARS-CoV-2E蛋白的C端PDZ结合基序分别与PALS1PDZ结构域有29.6和22.8μM亲和力，而MERS-CoV的相关序列不结合。然后我们测定了与SARS-CoV-1和SARS-CoV-2 E蛋白PDZ结合基序结合的PALS1 PDZ结构域的晶体结构。我们的发现为SARS-CoV-1/2介导的CRUMBS极性信号的颠覆奠定了结构基础，并为开发小分子抑制剂以抑制SARS-CoV-1/2介导的上皮细胞极性信号的破坏提供了平台。艾拉·贾沃斯基等人。给出了SARS-CoV-1和SARS-CoV-2E蛋白与PALS1PDZ结构域的复合体的晶体结构。他们的结果表明，冠状病毒E蛋白可以干扰正常的PALS1结合，潜在地破坏上皮组织的完整性，并可能为未来开发抗SARS-CoV-1/2的小分子抑制剂提供洞察力。
SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which is associated with severe and life-threatening pneumonia and respiratory failure. However, the molecular basis of these symptoms remains unclear. SARS-CoV-1 E protein interferes with control of cell polarity and cell-cell junction integrity in human epithelial cells by binding to the PALS1 PDZ domain, a key component of the Crumbs polarity complex. We show that C-terminal PDZ binding motifs of SARS-CoV-1 and SARS-CoV-2 E proteins bind the PALS1 PDZ domain with 29.6 and 22.8 μM affinity, whereas the related sequence from MERS-CoV did not bind. We then determined crystal structures of PALS1 PDZ domain bound to both SARS-CoV-1 and SARS-CoV-2 E protein PDZ binding motifs. Our findings establish the structural basis for SARS-CoV-1/2 mediated subversion of Crumbs polarity signalling and serve as a platform for the development of small molecule inhibitors to suppress SARS-CoV-1/2 mediated disruption of polarity signalling in epithelial cells. Airah Javorsky et al. present the crystal structures of SARS-CoV-1 and SARS-CoV-2 E proteins in complex with the PALS1 PDZ domain. Their results suggest that the coronavirus E protein can interfere with normal PALS1 binding, potentially disrupting epithelial tissue integrity, and may provide future insight into the development of small molecule inhibitors against SARS-CoV-1/2.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
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DOI：
10.1073/pnas.1416515111
发表时间：
2014-12-09
影响因子：
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影响因子：
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