Lee Woonghee, Tonelli Marco, Wu Chao, Aceti David J, Amarasinghe Gaya K, Markley John L
National Magnetic Resonance Facility at Madison, and Biochemistry Department, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI, 53706, USA.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Biomol NMR Assign. 2019 Oct;13(2):315-319. doi: 10.1007/s12104-019-09898-7. Epub 2019 May 10.
Ebola viral infections have resulted in several deadly epidemics in recent years in West and Central Africa. Because only one of the seven proteins encoded by the viral genome possesses enzymatic activity, disruption of protein-protein interactions is a promising route for antiviral drug development. We carried out a screening campaign to identify small, drug-like compounds that bind to the C-terminal region of the multifunctional Ebola nucleoprotein (eNP) with the objective of discovering ones that disrupt its binding to other Ebola proteins or to the single-stranded RNA genome. In the course of this effort we assigned the backbone H, N, and C resonances of residues 600‒739, the region that contains the critical eVP30 binding region 600‒615 targeted by host factors, and used the assigned chemical shifts to predict secondary structural features and peptide dynamics. This work supports and extends the previous X-ray crystal structures and NMR studies of residues 641‒739. We found that the 600‒739 domain consists of separate regions that are largely disordered and ordered.
近年来，埃博拉病毒感染在西非和中非引发了数次致命的疫情。由于病毒基因组编码的七种蛋白质中只有一种具有酶活性，破坏蛋白质-蛋白质相互作用是抗病毒药物开发的一条有前景的途径。我们开展了一项筛选活动，以鉴定与多功能埃博拉核蛋白（eNP）的C末端区域结合的小的、类药物化合物，目的是发现能够破坏其与其他埃博拉病毒蛋白或单链RNA基因组结合的化合物。在这项工作中，我们对600-739位残基的主链H、N和C共振进行了归属，该区域包含宿主因子靶向的关键eVP30结合区域600-615，并利用已归属的化学位移预测二级结构特征和肽动力学。这项工作支持并扩展了先前对641-739位残基的X射线晶体结构和核磁共振研究。我们发现，600-739结构域由 largely disordered 和有序的不同区域组成。
