The hepatitis B virus preS1 domain hijacks host trafficking proteins by motif mimicry.
Nat Chem Biol
; 9(9): 540-7, 2013 Sep.
Article
en En
| MEDLINE
| ID: mdl-23851574
ABSTRACT
Hepatitis B virus (HBV) is an infectious, potentially lethal human pathogen. However, there are no effective therapies for chronic HBV infections. Antiviral development is hampered by the lack of high-resolution structures for essential HBV protein-protein interactions. The interaction between preS1, an HBV surface-protein domain, and its human binding partner, γ2-adaptin, subverts the membrane-trafficking apparatus to mediate virion export. This interaction is a putative drug target. We report here atomic-resolution descriptions of the binding thermodynamics and structural biology of the interaction between preS1 and the EAR domain of γ2-adaptin. NMR, protein engineering, X-ray crystallography and MS showed that preS1 contains multiple γ2-EAR-binding motifs that mimic the membrane-trafficking motifs (and binding modes) of host proteins. These motifs localize together to a relatively rigid, functionally important region of preS1, an intrinsically disordered protein. The preS1-γ2-EAR interaction was relatively weak and efficiently outcompeted by a synthetic peptide. Our data provide the structural road map for developing peptidomimetic antivirals targeting the γ2-EAR-preS1 interaction.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Precursores de Proteínas
/
Virus de la Hepatitis B
/
Imitación Molecular
/
Subunidades gamma de Complejo de Proteína Adaptadora
/
Antígenos de Superficie de la Hepatitis B
Idioma:
En
Año:
2013
Tipo del documento:
Article