Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Cell Rep. 2019 Sep 24;28(13):3395-3405.e6. doi: 10.1016/j.celrep.2019.08.052.
Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into the human population in 2012 and has caused substantial morbidity and mortality. Potently neutralizing antibodies targeting the receptor-binding domain (RBD) on MERS-CoV spike (S) protein have been characterized, but much less is known about antibodies targeting non-RBD epitopes. Here, we report the structural and functional characterization of G2, a neutralizing antibody targeting the MERS-CoV S1 N-terminal domain (S1-NTD). Structures of G2 alone and in complex with the MERS-CoV S1-NTD define a site of vulnerability comprising two loops, each of which contain a residue mutated in G2-escape variants. Cell-surface binding studies and in vitro competition experiments demonstrate that G2 strongly disrupts the attachment of MERS-CoV S to its receptor, dipeptidyl peptidase-4 (DPP4), with the inhibition requiring the native trimeric S conformation. These results advance our understanding of antibody-mediated neutralization of coronaviruses and should facilitate the development of immunotherapeutics and vaccines against MERS-CoV.
中东呼吸综合征冠状病毒（MERS-CoV）于 2012 年进入人类群体，导致了大量的发病率和死亡率。针对 MERS-CoV 刺突（S）蛋白受体结合域（RBD）的强效中和抗体已经得到了描述，但针对非 RBD 表位的抗体知之甚少。在这里，我们报告了针对 MERS-CoV S1 N 端结构域（S1-NTD）的中和抗体 G2 的结构和功能特征。G2 单独和与 MERS-CoV S1-NTD 复合物的结构定义了一个包含两个环的脆弱部位，每个环都包含一个在 G2 逃逸变体中发生突变的残基。细胞表面结合研究和体外竞争实验表明，G2 强烈破坏了 MERS-CoV S 与其受体二肽基肽酶-4（DPP4）的结合，抑制作用需要天然三聚体 S 构象。这些结果推进了我们对冠状病毒抗体介导中和作用的理解，应该有助于开发针对 MERS-CoV 的免疫疗法和疫苗。
