6VSO

DengueV-2 Capsid Structure

Summary for 6VSO

• Entry DOI: 10.2210/pdb6vso/pdb
• Descriptor: Capsid premembrane protein, NITRATE ION, GLYCEROL, ... (4 entities in total)
• Functional Keywords: capsid, inhibitor, viral protein
• Biological source: Dengue virus 2
• Total number of polymer chains: 6
• Total formula weight: 57919.42

Authors

White, M.,Xia, H.,Shi, P. (deposition date: 2020-02-11, release date: 2020-07-15, Last modification date: 2023-10-11)

Primary citation

Xia, H.,Xie, X.,Zou, J.,Noble, C.G.,Russell, W.K.,Holthauzen, L.M.F.,Choi, K.H.,White, M.A.,Shi, P.Y.
A cocrystal structure of dengue capsid protein in complex of inhibitor.
Proc.Natl.Acad.Sci.USA, 117:17992-18001, 2020

PubMed Abstract: Dengue virus (DENV) was designated as a top 10 public health threat by the World Health Organization in 2019. No clinically approved anti-DENV drug is currently available. Here we report the high-resolution cocrystal structure (1.5 Å) of the DENV-2 capsid protein in complex with an inhibitor that potently suppresses DENV-2 but not other DENV serotypes. The inhibitor induces a "kissing" interaction between two capsid dimers. The inhibitor-bound capsid tetramers are assembled inside virions, resulting in defective uncoating of nucleocapsid when infecting new cells. Resistant DENV-2 emerges through one mutation that abolishes hydrogen bonds in the capsid structure, leading to a loss of compound binding. Structure-based analysis has defined the amino acids responsible for the inhibitor's inefficacy against other DENV serotypes. The results have uncovered an antiviral mechanism through inhibitor-induced tetramerization of the viral capsid and provided essential structural and functional knowledge for rational design of panserotype DENV capsid inhibitors.

PubMed: 32669438
DOI: 10.1073/pnas.2003056117

Experimental method

X-RAY DIFFRACTION (3.001 Å)