3ZHF

gamma 2 adaptin EAR domain crystal structure with preS1 site1 peptide NPDWDFN

Summary for 3ZHF

• Entry DOI: 10.2210/pdb3zhf/pdb
• Descriptor: AP-1 COMPLEX SUBUNIT GAMMA-LIKE 2, LARGE ENVELOPE PROTEIN, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• Functional Keywords: protein transport-viral protein complex, gae, protein transport/viral protein
• Biological source: Homo sapiens (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 14861.87

Authors

Juergens, M.C.,Voros, J.,Rautureau, G.,Shepherd, D.,Pye, V.E.,Muldoon, J.,Johnson, C.M.,Ashcroft, A.,Freund, S.M.V.,Ferguson, N. (deposition date: 2012-12-21, release date: 2013-07-10, Last modification date: 2024-11-20)

Primary citation

Jurgens, M.C.,Voros, J.,Rautureau, G.J.P.,Shepherd, D.A.,Pye, V.E.,Muldoon, J.,Johnson, C.M.,Ashcroft, A.E.,Freund, S.M.V.,Ferguson, N.
The Hepatitis B Virus Pres1 Domain Hijacks Host Trafficking Proteins by Motif Mimicry.
Nat.Chem.Biol., 9:540-, 2013

PubMed 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.

PubMed: 23851574
DOI: 10.1038/NCHEMBIO.1294

Experimental method

X-RAY DIFFRACTION (1.7 Å)