A cocrystal structure of dengue capsid protein in complex of inhibitor

Hongjie Xia, Xuping Xie, Jing Zou, Christian G. Noble, William K. Russell, Luis Marcelo F. Holthauzen, Kyung H. Choi, Mark A. White, Pei Yong Shi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)17992-18001
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number30
DOIs
StatePublished - Jul 28 2020

Keywords

  • Antiviral drug
  • Capsid
  • Dengue
  • Flavivirus
  • Virus assembly

ASJC Scopus subject areas

  • General

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