Structural highlights
Publication Abstract from PubMedHepatitis 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, gamma2-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 gamma2-adaptin. NMR, protein engineering, X-ray crystallography and MS showed that preS1 contains multiple gamma2-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-gamma2-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 gamma2-EAR-preS1 interaction. The hepatitis B virus preS1 domain hijacks host trafficking proteins by motif mimicry.,Jurgens MC, Voros J, Rautureau GJ, Shepherd DA, Pye VE, Muldoon J, Johnson CM, Ashcroft AE, Freund SM, Ferguson N Nat Chem Biol. 2013 Jul 14. doi: 10.1038/nchembio.1294. PMID:23851574[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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