Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Viruses. 2020 Nov 24;12(12):1346. doi: 10.3390/v12121346.
Zika virus (ZIKV), a mosquito-borne human flavivirus that causes microcephaly and other neurological disorders, has been a recent focus for the development of flavivirus vaccines and therapeutics. We report here a 4.0 Å resolution structure of the mature ZIKV in complex with ADI-30056, a ZIKV-specific human monoclonal antibody (hMAb) isolated from a ZIKV infected donor with a prior dengue virus infection. The structure shows that the hMAb interactions span across the E protein dimers on the virus surface, inhibiting conformational changes required for the formation of infectious fusogenic trimers similar to the hMAb, ZIKV-117. Structure-based functional analysis, and structure and sequence comparisons, identified ZIKV residues essential for neutralization and crucial for the evolution of highly potent E protein crosslinking Abs in ZIKV. Thus, this epitope, ZIKV's "Achilles heel", defined by the contacts between ZIKV and ADI-30056, could be a suitable target for the design of therapeutic antibodies.
寨卡病毒（ZIKV）是一种通过蚊子传播的人类黄病毒，可导致小头症和其他神经系统疾病，一直是黄病毒疫苗和疗法开发的重点。我们在此报告了成熟的 ZIKV 与 ADI-30056 的 4.0 Å 分辨率结构复合物，ADI-30056 是一种从先前感染过登革热病毒的 ZIKV 感染者中分离出来的 ZIKV 特异性人源单克隆抗体（hMAb）。该结构表明，hMAb 的相互作用跨越病毒表面的 E 蛋白二聚体，抑制了形成感染性融合三聚体所需的构象变化，类似于 hMAb、ZIKV-117。基于结构的功能分析以及结构和序列比较，确定了 ZIKV 中和所必需的残基，这些残基对于 ZIKV 中高度有效的 E 蛋白交联 Abs 的进化至关重要。因此，这个由 ZIKV 和 ADI-30056 之间的接触所定义的表位是“阿喀琉斯之踵”，可能是设计治疗性抗体的合适靶标。
