Unique structural features of flaviviruses’ capsid proteins: new insights on structure-function relationship

The interaction of dengue virus capsid protein with negatively charged interfaces drives the in vitro assembly of nucleocapsid-like particles

“…DENVC is a small (100 residues) and highly basic protein with very particular structural features [ 22 , 23 ]. It forms homodimers in solution, containing an N-terminal intrinsically disordered region (IDR), followed by 4 inter-twined α-helices connected by short loops, with the tridimensional structure maintained mainly by quaternary contacts [ 22 , 23 ]. Currently, the most accepted packaging model of the DENV genome is based on an asymmetric charge distribution on the DENVC surface.…”

“…Currently, the most accepted packaging model of the DENV genome is based on an asymmetric charge distribution on the DENVC surface. The presence of 11 apolar residues in the helix α2 generates a hydrophobic cleft in one protein face, while the solvent-exposed region of α4/α4´, rich in basic residues, would act as the RNA binding site [ 16 , 19 , 22 – 24 ]. However, a more accurate analysis of the electrostatic surface potential of flaviviruses’ C proteins reveals a highly electropositive surface throughout the protein [ 22 ].…”

Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein

“…The α2-α2' is nonpolar and along with α1 and α1' form a concave-shaped hydrophobic cleft, that interacts with the viral membrane. The dynamics, size, and orientation of α1 and α1' regulate the exposure of the hydrophobic surface 5 , 6 . Among flaviviruses, α2-α2' is the most conserved region of protein C, helping in the formation of a conserved hydrophobic surface (π-stacked Phe53/Phe53’, Phe47, Leu54, and Leu57) and a conserved aromatic backbone (π-stacked Phe56/Phe84’ and Phe56’/Phe84) 6 .…”

Editorial overview: Special issue on virus structure and expression in current opinion in virology

“…The authors and their published researchers have reviewed technological and methodological advances on viral structure and expression in this current issue. The most advanced experimental techniques used to characterize virus particles and virus proteins, including cryogenic electronic microscopy and nuclear magnetic resonance, were thoroughly reviewed [ 1 , 2 ]; new developments in molecular dynamics simulation and other computational strategies to study virus structure and proteins were also described [ 3 ]; an elegant integrative approach combining experimental and computational methods to characterize at atomic-level the structures and dynamics of HIV-1 capsids were carefully shown [ 4 ]; pivotal examples of the structure and functional characterization of important targets for antiviral development against SARS-CoV 2 and flaviviruses were described [ 5 , 6 , 7 ]. Also, discoveries on giant viruses, which have recently shaken the virology community, were aborded, and revisions on important viral protein drug targets were made [ 8 , 9 ].…”

“…The contributions of Hillen [ 5 ], da Poian et al [ 7 ], and Moraes et al [ 6 ] exemplified the considerable impact the structural virology is providing to fight global-impacting viruses: the SARS-CoV 2, the HIV-1, and flaviviruses. Hillen [ 5 ] reviewed the structure and function of SARS-CoV 2 polymerase, one of the most promising drug targets against SARS-CoV 2, and organized an overview of current coronavirus RdRp structures, together with many functional studies; Da Poian et al [ 7 ] reviewed the structure and function of flaviviruses’ capsid proteins that interact with viral RNA to form the flaviviruses nucleocapsid. They showed how vital the quaternary organization and the dynamics of the flaviviruses’ capsid proteins are for its function and virion morphogenesis.…”