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Open AccessArticle

Structural and Functional Properties of the Capsid Protein of Dengue and Related Flavivirus

1
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal
2
Centro de Química-Física Molecular, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisbon, Portugal
*
Authors to whom correspondence should be addressed.
Present address: Instituto de Biologia Experimental e Tecnológica (iBET), Apartado 12, 2780-901 Oeiras, Portugal.
Present address: Department of Biophysical Chemistry, J. Heyrovský Institute of Physical Chemistry, Czech Academy of Sciences, Dolejškova 3, 182 23 Prague 8, Czech Republic.
Int. J. Mol. Sci. 2019, 20(16), 3870; https://doi.org/10.3390/ijms20163870
Received: 21 June 2019 / Revised: 5 August 2019 / Accepted: 6 August 2019 / Published: 8 August 2019
Dengue, West Nile and Zika, closely related viruses of the Flaviviridae family, are an increasing global threat, due to the expansion of their mosquito vectors. They present a very similar viral particle with an outer lipid bilayer containing two viral proteins and, within it, the nucleocapsid core. This core is composed by the viral RNA complexed with multiple copies of the capsid protein, a crucial structural protein that mediates not only viral assembly, but also encapsidation, by interacting with host lipid systems. The capsid is a homodimeric protein that contains a disordered N-terminal region, an intermediate flexible fold section and a very stable conserved fold region. Since a better understanding of its structure can give light into its biological activity, here, first, we compared and analyzed relevant mosquito-borne Flavivirus capsid protein sequences and their predicted structures. Then, we studied the alternative conformations enabled by the N-terminal region. Finally, using dengue virus capsid protein as main model, we correlated the protein size, thermal stability and function with its structure/dynamics features. The findings suggest that the capsid protein interaction with host lipid systems leads to minor allosteric changes that may modulate the specific binding of the protein to the viral RNA. Such mechanism can be targeted in future drug development strategies, namely by using improved versions of pep14-23, a dengue virus capsid protein peptide inhibitor, previously developed by us. Such knowledge can yield promising advances against Zika, dengue and closely related Flavivirus. View Full-Text
Keywords: Dengue virus (DENV); capsid protein (C protein); Flavivirus; intrinsically disordered protein (IDP); protein–RNA interactions; protein–host lipid systems interaction; circular dichroism; time-resolved fluorescence anisotropy Dengue virus (DENV); capsid protein (C protein); Flavivirus; intrinsically disordered protein (IDP); protein–RNA interactions; protein–host lipid systems interaction; circular dichroism; time-resolved fluorescence anisotropy
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Faustino, A.F.; Martins, A.S.; Karguth, N.; Artilheiro, V.; Enguita, F.J.; Ricardo, J.C.; Santos, N.C.; Martins, I.C. Structural and Functional Properties of the Capsid Protein of Dengue and Related Flavivirus. Int. J. Mol. Sci. 2019, 20, 3870.

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