title: The hepatitis B virus preS1 domain hijacks host trafficking proteins by motif mimicry.
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.
authors.affiliation: 1] School of Medicine and Medical Science, University College Dublin, Dublin, Ireland. [2].
authors.forename: Maike C
authors.initials: MC
authors.lastname: Jürgens
authors.forename: Judit
authors.initials: J
authors.lastname: Vörös
authors.forename: Gilles J P
authors.initials: GJ
authors.lastname: Rautureau
authors.forename: Dale A
authors.initials: DA
authors.lastname: Shepherd
authors.forename: Valerie E
authors.initials: VE
authors.lastname: Pye
authors.forename: Jimmy
authors.initials: J
authors.lastname: Muldoon
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Johnson
authors.forename: Alison E
authors.initials: AE
authors.lastname: Ashcroft
authors.forename: Stefan M V
authors.initials: SM
authors.lastname: Freund
authors.forename: Neil
authors.initials: N
authors.lastname: Ferguson
mesh_terms: D033982:Adaptor Protein Complex gamma Subunits / Q000737:chemistry / Q000378:metabolism*; D020816:Amino Acid Motifs; D006514:Hepatitis B Surface Antigens / Q000737:chemistry* / Q000378:metabolism*; D006515:Hepatitis B virus / Q000378:metabolism*; D018716:Molecular Mimicry; D011498:Protein Precursors / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D033982:Adaptor Protein Complex gamma Subunits; D006514:Hepatitis B Surface Antigens; D011498:Protein Precursors; C050806:presurface protein 1, hepatitis B surface antigen