PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

Related Articles
Protein Folding and Misfolding: It's the Journey, Not the Destination
March 2015
CCR5 and HIV Infection
January 2015
HIV/AIDS: Pre-fusion Env Exposed
January 2015
HIV/AIDS: Slide to Enter
January 2015
Updating ModBase
January 2015
Power in Numbers
August 2014
Quorum Sensing: A Groovy New Component
August 2014
Bacterial CDI Toxins
June 2014
Immunity: One Antibody to Rule Them All
June 2014
Virology: A Bat Influenza Hemagglutinin
March 2014
Virology: Making Sensitive Magic
March 2014
Virology: Visualizing Cyanophage Assembly
March 2014
Virology: Zeroing in on HBV Egress
March 2014
March 2014
Cas4 Nuclease and Bacterial Immunity
February 2014
Microbial Pathogenesis: A GNAT from Pseudomonas
February 2014
Microbial Pathogenesis: Targeting Drug Resistance in Mycobacterium tuberculosis
February 2014
Microbiome: The Dynamics of Infection
September 2013
Membrane Proteome: A Funnel-like Viroporin
August 2013
Infectious Diseases: A Pathogen Ubiquitin Ligase
May 2013
Infectious Diseases: A Shared Syringe
May 2013
Infectious Diseases: Determining the Essential Structome
May 2013
Infectious Diseases: Targeting Meningitis
May 2013
NDM-1 and Antibiotics
May 2013
Bacterial Hemophores
January 2013
Microbial Pathogenesis: Computational Epitope Prediction
January 2013
Microbial Pathogenesis: Influenza Inhibitor Screen
January 2013
Microbial Pathogenesis: Measles Virus Attachment
January 2013
Microbial Pathogenesis: NEAT Iron
January 2013
Membrane Proteome: Sphingolipid Synthesis Selectivity
December 2012
A signal sensing switch
September 2012
Gauging needle structure
July 2012
Anthrax Stealth Siderophores
June 2012
A Pseudomonas L-serine dehydrogenase
May 2012
Pilus Assembly Protein TadZ
April 2012
Making Lipopolysaccharide
January 2012
Superbugs and Antibiotic Resistance
December 2011
A change to resistance
November 2011
An effective and cooperative dimer
November 2011
The Perils of Protein Secretion
November 2011
Bacterial Armor
October 2011
Breaking down the defenses
September 2011
Moving some metal
August 2011
Capsid assembly in motion
April 2011
Know thy enemy … structurally
October 2010
Treating sleeping sickness
May 2010
Bacterial spore kinase
April 2010
Hemolysin BL
January 2010
Unusual cell division
October 2009
Anthrax evasion tactics
September 2009
Toxin-antitoxin VapBC-5
September 2009
Antibiotic target
August 2009
July 2009
Tackling influenza
June 2009
You look familiar: the Type VI secretion system
June 2009
Unique SARS
April 2009
Anthrax stealth molecule
March 2009
A new class of bacterial E3 ubiquitination enzymes
January 2009
Antiviral evasion
October 2008
SARS connections
September 2008
SARS Coronavirus Nonstructural Protein 1
June 2008

Research Themes Infectious diseases

Virology: Zeroing in on HBV Egress

SBKB [doi:10.1038/sbkb.2012.189]
Featured Article - March 2014
Short description: Crystal structures of human γ2-adaptin in complex with a peptide from HBV preS1 suggest a path to antivirals.

Surface representation of the structure of human γ2-EAR in complex with the preS1(29–36) peptide (PDB 3ZHF). 1

Hepatitis B virus (HBV) is a potentially lethal liver disease that currently affects over 300 million people worldwide. While protective vaccines are available, there is still no effective treatment for chronic HBV infections. Thus, the development of new antiviral therapies remains an important goal, for which a detailed understanding of host-virus interactions is critical.

During viral maturation and egress, HBV is enveloped by a lipid membrane while transiting through the secretory pathway. This process is dependent on the interaction between the preS1-domain of the long isoform of HBV's surface antigen (HBsAg) protein and the host protein γ2-adaptin. The preS1-domain is exposed on the cytosolic side of the endoplasmic reticulum membrane prior to virion envelopment, and becomes displayed on the surface of the mature virus. Ferguson and colleagues (PSI MPID) recently investigated the interaction between the HBsAg preS1-domain and γ2-adaptin EAR domain (γ2-EAR); the latter is responsible for binding to accessory proteins in the secretory pathway.

First, the authors used NMR spectroscopy to map the interaction surfaces on preS1 and γ2-EAR. Chemical shift perturbations in γ2-EAR were located on a surface equivalent to that of previously mapped peptide-EAR domain interactions. Within preS1, the interaction was located in a linear motif encompassing residues 29–41, with further analyses narrowing this to residues 29–36, a sequence with similarities to canonical EAR-binding motifs.

To obtain a detailed view of the interaction, γ2-EAR was crystalized in its apo form (PDB 4BCX) or bound to either a high-affinity ligand peptide obtained through phage-display screening (PDB 2YMT) or a peptide corresponding to preS1 residues 29–36 (PDB 3ZHF). The structures were solved to resolutions of 2.0, 1.8 and 1.7 Å, respectively. The binding mode of preS1 to γ2-EAR mimicked a two-pin plug motif, with two tryptophan residues separated by a single amino acid instead of the two-residue spacer observed in the canonical interaction with the phage peptide. This binding mode was made possible by a compensating rearrangement within the binding site on γ2-EAR. While NMR and affinity measurements also suggested additional interaction sites on preS1, the phage-derived peptide was sufficient to effectively prevent binding of the full-length preS1 protein to γ2-EAR in vitro.

These findings indicate that HBV interaction with γ2-adaptin—an essential element of virus propagation—could effectively be targeted by a small peptide, suggesting a path for the development of drugs aimed at restricting HBV's access to the cellular trafficking machinery.

Stéphane Larochelle


  1. M.C. Jürgens et al. The hepatitis b virus preS1 domain hijacks host trafficking proteins by motif mimicry.
    Nat Chem Biol. 9, 540-547 (2013). doi:10.1038/nchembio.1294

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health