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

Immunity: One Antibody to Rule Them All

SBKB [doi:10.1038/sbkb.2014.204]
Featured Article - June 2014
Short description: Structural studies of antibody F045–092 explain its ability to neutralize all H3-subtype influenza strains.

Crystal structures of F045–092 Fab in complex with Vic1975/H3 HA (left, PDB 4O58) and Vic2011/H3 HA (right, PDB 4O5I). One HA protomer is in blue and green, Fab in purple and pink. Glycans are shown as spheres in yellow, orange and blue 1 .

Each year seasonal flu infects millions of people worldwide, with severe health and economic consequences. Although vaccination can be effective in preventing the spread of the flu, the constantly changing virus requires annual reformulation of the vaccine. Part of this challenge comes from the hyper-variable influenza's hemagglutinin (HA) surface glycoprotein, which initiates infection by binding to sialic acid glycans on host cells. A small number of neutralizing antibodies show broad activity in inhibiting HA-receptor interaction across many HA subtypes. Antibody F045–092, for example, has neutralizing activity against all H3N2 strains from 1968 to 2004, as well as against certain H1N1, H2N2 and H5N1 viruses.

To understand the structural basis for the broad activity of F045–092, Wilson and colleagues used the JCSG crystallization pipeline and solved the crystal structures of its fragment antigen-binding (Fab) in complex with HAs from two H3 subtypes: A/Victoria/3/1975 (Vic1975/H3; PDB 4O58) and A/Victoria/361/2011 (Vic2011/H3; PDB 4O5I). These structures show that the F045–092 complementarity determining region loop HCDR3 consists of four residues that chemically resemble sialic acid and form the same network of hydrogen bonds used by HA to recognize its cellular target. Alanine scanning mutagenesis of HCDR3 abolished binding of the F045–092 Fab to nearly all H3 strains tested, suggesting that the antibody's mimicry of sialic acid is crucial in the recognition of H3 HA.

In addition to its direct interactions with the sialic acid-binding pocket, F045–092 makes contacts with residues that are absolutely conserved in all H3 HAs (namely Ser136 and Trp153), helping explain the antibody's specificity for the H3 subtype. Notably, F045–092 does not make contact with any of the N-linked glycosylation sites on the Vic1975/H3 or Vic2011/H3 heads, which have seven and twelve glycans, respectively. The avoidance of these sites allows the antibody to maintain binding efficacy within the H3 subtype, despite the evolutionary accretion of glycosylation sites over time.

Overall, these structures show how a single antibody can neutralize many HA targets from the same subfamily, and may allow for the development of small-molecule inhibitors or immunogens against all H3 viruses.

Timothy Silverstein


  1. P.S. Lee et al. Receptor mimicry by antibody F045–092 facilitates universal binding to the H3 subtype of influenza virus.
    Nat Commun. 5, 3614 (2014). doi:10.1038/ncomms4614

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