Abstract
Anthrax toxin receptor 1 (ANTXR1), also known as Tumor Endothelial Marker 8, is overexpressed on the surface of tumor cells in over 60% of human cancers. A serious drawback for developing specific ligands for targeted therapy against ANTXR1 is the cross-reactivity with ANTXR2. Recently, ANTXR1 was identified as the high-affinity cellular receptor for Seneca Valley Virus (SVV). SVV has shown promising results as an oncolytic agent in clinical trials, and this discovery offers a powerful biomarker for selecting patient response to treatment. The identification of specific interaction sites between SVV and ANTXR1 lays the foundation to construct potent virus mutants with specific cancer tropism that can escape host antibody response and to expand the development of both antiangiogenic and anticancer antibody therapy.
Recently, the use of oncolytic viruses in cancer therapy has become a realistic therapeutic option. Seneca Valley Virus (SVV) is a newly discovered picornavirus, which has earned a significant reputation as a potent oncolytic agent. Anthrax toxin receptor 1 (ANTXR1), one of the cellular receptors for the protective antigen secreted by
Bacillus anthracis
, has been identified as the high-affinity cellular receptor for SVV. Here, we report the structure of the SVV-ANTXR1 complex determined by single-particle cryo-electron microscopy analysis at near-atomic resolution. This is an example of a shared receptor structure between a mammalian virus and a bacterial toxin. Our structure shows that ANTXR1 decorates the outer surface of the SVV capsid and interacts with the surface-exposed BC loop and loop II of VP1, “the puff” of VP2 and “the knob” of VP3. Comparison of the receptor-bound capsid structure with the native capsid structure reveals that receptor binding induces minor conformational changes in SVV capsid structure, suggesting the role of ANTXR1 as an attachment receptor. Furthermore, our results demonstrate that the capsid footprint on the receptor is not conserved in anthrax toxin receptor 2 (ANTXR2), thereby providing a molecular mechanism for explaining the exquisite selectivity of SVV for ANTXR1.