Pre-Fusion and Fusion Structure of ZIKV E == The basic unit of ZIKV E, on the basis of structures derived from X-ray crystallography and cryo-EM (PDB accession codes 5JHM and 5LBS), shows the protein in a head-to-tail dimer arrangement (Figure 2a). of viral host entry. Keywords:EBOV GP, ZIKV E, pre-fusion-to-fusion transition, antibody binding == 1. Introduction == Enveloped viruses employ a common mechanism to enter the host cell [1]. The first steps, receptor binding and membrane fusion, are initiated by the envelope protein [2,3,4]. While specific details vary among different viruses, the envelope proteins invariably go through a large conformational change [5,6] before initiating membrane fusion. These large conformational changes allow the envelope protein MPC-3100 to assume an extended fusion-initiation conformation: the envelope protein in the fusion-initiation state is able to bridge across the viral and the host membranes, subsequently bringing the two membranes into close proximity and starting the fusion process [7,8]. Viral neutralization by antibodies may involve binding to the fusion-state structure or inhibiting its formation. Rabbit Polyclonal to SH2D2A Therefore, viral envelope proteins are important foci for the development of vaccines and therapeutics. Recent intense research focus on the Ebola and Zika viruses has provided new data for the structural modeling of these transitions. Structural data for a number of viral envelope proteins are available in the Protein Data Bank (PDB) [6,9]. Many of these known structures correspond to envelope proteins in the pre-fusion state, and some of the fusion-state structures only correspond to a partial molecule (usually in a low-pH environment). To date, there are no structures for complete viral envelope proteins in the fusion-initiation state; understanding the mechanics of the conformational change from MPC-3100 the pre-fusion to the fusion-initiation state requires such a description. Directly determining fusion-state structures for complete viral envelope proteins by experimental methods is difficult; molecular modeling offers a readily applicable alternative means to structural characterization. We describe the use of a knowledge-based methodology (homology modeling) to develop structures of viral envelope proteins in the fusion-initiation state. We further extend the basic idea of homology modeling to include a simple concept, proteins and protein domains that fold similarly interact similarly, as a result, developing structural models of envelope proteinantibody complexes. In this work we focus on envelope proteins from Ebola and Zika viruses. Ebola virus causes Ebola hemorrhagic fever, a severe and highly lethal infection: the 20132015 West African Ebola virus epidemic (December 20132015) resulted in approximately 11,000 confirmed deaths and 28,000 suspected cases [10]. Zika virus is a member of the virus family Flaviviridae [11,12] that includes the Dengue virus (DENV) and West Nile virus; in contrast to the above-mentioned Ebola virus, Zika virus causes a brief, relatively mild illness, but it has been linked to congenital microcephaly and GuillanBarr Syndrome MPC-3100 in humans [13,14]. In mouse models, Zika virus causes microcephaly [15], as well as damage to the male reproductive system [16] and to adult neural stem cells [17]. At the time of publication, 84 countries, territories, and subnational areas reported Zika transmission [18]. The Ebola and Zika viruses represent persistent threats to public health; there are limited options available for the treatment or prevention of either virus. In this paper, we present the following models for Ebola virus glycoprotein (EBOV GP) and Zika virus envelope protein (ZIKV E): A trimer model of EBOV GP in the fusion-initiation state with the NiemannPick C1 (NPC1) receptor and neutralizing antibodies. A trimer model of ZIKV E in the fusion-initiation state with neutralizing antibodies and the surrounding 9-mer structure of ZIKV E in the MPC-3100 pre-fusion state with neutralizing antibodies. Our modeling approach is general and comprehensive and can be used for developing.