Structural Transition and Antibody Binding of EBOV GP and ZIKV E Proteins from Pre-Fusion to Fusion-Initiation State

Abstract

Membrane fusion proteins are responsible for viral entry into host cells—a crucial first step in viral infection. These proteins undergo large conformational changes from pre-fusion to fusion-initiation structures, and, despite differences in viral genomes and disease etiology, many fusion proteins are arranged as trimers. Structural information for both pre-fusion and fusion-initiation states is critical for understanding virus neutralization by the host immune system. In the case of Ebola virus glycoprotein (EBOV GP) and Zika virus envelope protein (ZIKV E), pre-fusion state structures have been identified experimentally, but only partial structures of fusion-initiation states have been described. While the fusion-initiation structure is in an energetically unfavorable state that is difficult to solve experimentally, the existing structural information combined with computational approaches enabled the modeling of fusion-initiation state structures of both proteins. These structural models provide an improved understanding of four different neutralizing antibodies in the prevention of viral host entry.

Real-Time Analysis of Individual Ebola Virus Glycoproteins Reveals Pre-Fusion, Entry-Relevant Conformational Dynamics

“…This rearrangement may aid in priming GP1 for interaction with NPC1, and in facilitating other downstream events related to fusion. Recent structural modeling suggests that movement of the fusion loop away from the surface of the virion would require outward motion of GP1, but not necessarily GP1 release, in order to allow the fusion loop access to the space above the GP core [39]. Our results confirm that GP1 does not dissociate from GP2 at this stage, since we still observe reversible transitions into and out of intermediate FRET.…”

Modeling the Influenza A NP-vRNA-Polymerase Complex in Atomic Detail

“…Additional sequence information from GenBank [ 7 ] or the Influenza Virus Resource [ 19 ] can also be used to modify structures by mutating select residues, and allowing mutational assays to be investigated in silico. Macromolecular assembly, as we have shown here and in the past [ 11 , 13 , 14 , 15 ], is particularly well-suited for assembling large complexes in atomic detail, shedding light on how the component molecules are arranged relative to one another, and how particular interactions can stabilize these assemblies.…”

“…Macromolecular complexes can be generated with sufficient accuracy to accomplish these goals using the vast amount of sequence and structure information collected by the biosciences community [ 7 , 8 , 9 , 10 ], and with directed homology modeling methods such as motif-matching fragment assembly (MMFA). Our group has employed MMFA methods to generate models of T. thermophilus ribosome [ 11 , 12 ], ribosomal subunits of E. coli [ 13 ], viral envelope proteins from Zika and Ebola viruses [ 14 ], and E. coli transcription initiation complexes [ 15 ]. In each of these studies, we modeled the complexes at atomic precision and predicted interactions responsible for functional behaviors.…”