A cocrystal structure of dengue capsid protein in complex of inhibitor
| Autor: | William K. Russell, Hongjie Xia, Christian G. Noble, Mark A. White, Pei Yong Shi, Luis Marcelo F. Holthauzen, Kyung H. Choi, Jing Zou, Xuping Xie |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Protein Conformation medicine.drug_class viruses Dengue virus medicine.disease_cause Antiviral Agents Dengue fever Structure-Activity Relationship medicine Protein Interaction Domains and Motifs Amino Acid Sequence Nucleocapsid chemistry.chemical_classification Mutation Binding Sites Multidisciplinary biology Rational design virus diseases Dengue Virus Biological Sciences biochemical phenomena metabolism and nutrition biology.organism_classification medicine.disease Virology Amino acid Flavivirus chemistry Capsid Capsid Proteins Antiviral drug Protein Binding |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|