An inter-residue network model to identify mutational-constrained regions on the Ebola coat glycoprotein.
An inter-residue network model to identify mutational-constrained regions on the Ebola coat glycoprotein.
复制标题
DOI：
10.1038/srep45886
复制
发表时间：
2017-04-11
影响因子：
4.6
通讯作者：
Sasisekharan R
中科院分区：
文献类型：
--
作者：
Quinlan DS;Raman R;Tharakaraman K;Subramanian V;Del Hierro G;Sasisekharan R
最近，针对埃博拉外壳糖蛋白（GP）的疫苗和单克隆抗体鸡尾酒的开发取得了进展。基于埃博拉病毒的自然序列进化的突变率，这些治疗策略可能会施加额外的选择压力，以驱动GP中逃避中和的突变的获取。鉴于埃博拉病毒GP之间的序列高度保守，确定对疫苗或单克隆抗体单一或混合治疗产生突变的倾向将具有挑战性。在这项研究中，我们使用一种方法分析了每个残基的易变性，该方法基于三聚体GP三维结构中残基相互作用网络的程度来捕获易变性的结构约束。该分析显示沿GP1-GP2界面有两个不同的高度联网残基簇，其中一部分与已知中和抗体的表位表面重叠。这种网络方法还允许我们在不同抗埃博拉抗体的已知热点残基网络中识别其他残基，这些残基将影响抗体-表位相互作用。
Recently, progress has been made in the development of vaccines and monoclonal antibody cocktails that target the Ebola coat glycoprotein (GP). Based on the mutation rates for Ebola virus given its natural sequence evolution, these treatment strategies are likely to impose additional selection pressure to drive acquisition of mutations in GP that escape neutralization. Given the high degree of sequence conservation among GP of Ebola viruses, it would be challenging to determine the propensity of acquiring mutations in response to vaccine or treatment with one or a cocktail of monoclonal antibodies. In this study, we analyzed the mutability of each residue using an approach that captures the structural constraints on mutability based on the extent of its inter-residue interaction network within the three-dimensional structure of the trimeric GP. This analysis showed two distinct clusters of highly networked residues along the GP1-GP2 interface, part of which overlapped with epitope surfaces of known neutralizing antibodies. This network approach also permitted us to identify additional residues in the network of the known hotspot residues of different anti-Ebola antibodies that would impact antibody-epitope interactions.