title: Antibody Binding Modulates Conformational Exchange in Domain III of Dengue Virus E Protein.
abstract: Domain III of dengue virus E protein (DIII) participates in the recognition of cell receptors and in structural rearrangements required for membrane fusion and ultimately viral infection; furthermore, it contains epitopes for neutralizing antibodies and has been considered a potential vaccination agent. In this work, we addressed various structural aspects of DIII and their relevance for both the dengue virus infection mechanism and antibody recognition. We provided a dynamic description of DIII at physiological and endosomal pHs and in complex with the neutralizing human antibody DV32.6. We observed conformational exchange in the isolated DIII, in regions important for the packing of E protein dimers on the virus surface. This conformational diversity is likely to facilitate the partial detachment of DIII from the other E protein domains, which is required to achieve fusion to the host cellular membranes and to expose the epitopes of many anti-DIII antibodies. A comparison of DIII of two dengue virus serotypes revealed many common features but also some possibly unexpected differences. Antibody binding to DIII of dengue virus serotype 4 attenuated the conformational exchange in the epitope region but, surprisingly, generated exchange in other parts of DIII through allosteric effects.
  
  
  OBJECTIVE
  Many studies have provided extensive structural information on the E protein and particularly on DIII, also in complex with antibodies. However, there is very scarce information regarding the molecular dynamics of DIII, and almost nothing is available on the dynamic effect of antibody binding, especially at the quantitative level. This work provides one of the very rare descriptions of the effect of antibody binding on antigen dynamics.
authors.affiliation: National NMR Center CNRMN, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Adolfo H
authors.initials: AH
authors.lastname: Moraes
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana (USI), Bellinzona, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Simonelli
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana (USI), Bellinzona, Switzerland.
authors.forename: Mattia
authors.initials: M
authors.lastname: Pedotti
authors.affiliation: National NMR Center CNRMN, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Fabio C L
authors.initials: FC
authors.lastname: Almeida
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana (USI), Bellinzona, Switzerland luca.varani@irb.usi.ch valente@cnrmn.bioqmed.ufrj.br.
authors.forename: Luca
authors.initials: L
authors.lastname: Varani
authors.affiliation: National NMR Center CNRMN, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil luca.varani@irb.usi.ch valente@cnrmn.bioqmed.ufrj.br.
authors.forename: Ana P
authors.identifier: http://orcid.org/0000-0001-7219-1123
authors.initials: AP
authors.lastname: Valente
mesh_terms: D057134:Antibodies, Neutralizing / Q000378:metabolism*; D000914:Antibodies, Viral / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014759:Viral Envelope Proteins; C466981:glycoprotein E, dengue virus type 4