Molecular Biology and Virology Research Laboratory, Department of Medical Biosciences, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa.
South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa.
Viruses. 2022 Aug 2;14(8):1707. doi: 10.3390/v14081707.
The less virulent human (h) coronaviruses (CoVs) 229E, NL63, OC43, and HKU1 cause mild, self-limiting respiratory tract infections, while the more virulent SARS-CoV-1, MERS-CoV, and SARS-CoV-2 have caused severe outbreaks. The CoV envelope (E) protein, an important contributor to the pathogenesis of severe hCoV infections, may provide insight into this disparate severity of the disease. We, therefore, generated full-length E protein models for SARS-CoV-1 and -2, MERS-CoV, HCoV-229E, and HCoV-NL63 and docked C-terminal peptides of each model to the PDZ domain of the human PALS1 protein. The PDZ-binding motif (PBM) of the SARS-CoV-1 and -2 and MERS-CoV models adopted a more flexible, extended coil, while the HCoV-229E and HCoV-NL63 models adopted a less flexible alpha helix. All the E peptides docked to PALS1 occupied the same binding site and the more virulent hCoV E peptides generally interacted more stably with PALS1 than the less virulent ones. We hypothesize that the increased flexibility of the PBM in the more virulent hCoVs facilitates more stable binding to various host proteins, thereby contributing to more severe disease. This is the first paper to model full-length 3D structures for both the more virulent and less virulent hCoV E proteins, providing novel insights for possible drug and/or vaccine development.
低致病性人冠状病毒（hCoV）229E、NL63、OC43 和 HKU1 引起轻度、自限性呼吸道感染，而高致病性 SARS-CoV-1、MERS-CoV 和 SARS-CoV-2 已导致严重爆发。冠状病毒包膜（E）蛋白是严重 hCoV 感染发病机制的重要因素，可能为疾病的严重程度差异提供线索。因此，我们生成了 SARS-CoV-1 和 -2、MERS-CoV、HCoV-229E 和 HCoV-NL63 的全长 E 蛋白模型，并将每个模型的 C 端肽对接至人 PALS1 蛋白的 PDZ 结构域。SARS-CoV-1 和 -2 以及 MERS-CoV 模型的 PDZ 结合基序（PBM）采用更灵活、扩展的线圈，而 HCoV-229E 和 HCoV-NL63 模型采用不太灵活的α螺旋。所有 E 肽都对接至 PALS1 并占据相同的结合位点，且高致病性 hCoV 的 E 肽通常比低致病性的 E 肽与 PALS1 相互作用更稳定。我们假设高致病性 hCoV 中 PBM 的灵活性增加有助于与各种宿主蛋白更稳定地结合，从而导致更严重的疾病。这是第一篇对高致病性和低致病性 hCoV E 蛋白全长 3D 结构进行建模的论文，为可能的药物和/或疫苗开发提供了新的见解。
