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Structural Basis for a Switch in Receptor Binding Specificity of Two H5N1 Hemagglutinin Mutants.

Xueyong Zhu1 Karthik Viswanathan2 Rahul Raman2 Wenli Yu1 Ram Sasisekharan3 Ian A Wilson4,5
Affiliations 5 institutions
  1. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  2. Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  3. Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].
  4. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
  5. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
PMID 26586437 2015 Cell Rep eng ppublish
PubMed DOI Browse context

Article

Publication summary

Avian H5N1 influenza viruses continue to spread in wild birds and domestic poultry with sporadic infection in humans. Receptor binding specificity changes are a prerequisite for H5N1 viruses and other zoonotic viruses to be transmitted among humans. Previous reported hemagglutinin (HA) mutants from ferret-transmissible H5N1 viruses of A/Vietnam/1203/2004 and A/Indonesia/5/2005 showed slightly increased, but still very weak, binding to human receptors. From mutagenesis and glycan array studies, we previously identified two H5N1 HA mutants that could more effectively switch receptor specificity to human-like α2-6-linked sialosides with avidity comparable to wild-type H5 HA binding to avian-like α2-3-linked sialosides. Here, crystal structures of these two H5 HA mutants free and in complex with human and avian glycan receptor analogs reveal the structural basis for their preferential binding to human receptors. These findings suggest continuous surveillance should be maintained to monitor and assess human-to-human transmission potential of H5N1 viruses.

crystal structure glycan complex H5N1 influenza virus hemagglutinin receptor binding specificity transmission Animals Birds Crystallography, X-Ray Hemagglutinins Humans Influenza A Virus, H5N1 Subtype Mutation Polysaccharides Protein Binding Receptors, Cell Surface

Structured evidence records

Evidence records

2 total
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.95
Key finding

Mutations in H5N1 hemagglutinin enabled a switch in receptor binding specificity from avian-type α2-3-linked to human-type α2-6-linked sialosides, demonstrating molecular adaptation toward human receptor usage.

Virus
IAV H5N1
Host
Not specified
Location
Not specified
Supporting text

Two H5N1 HA mutants could more effectively switch receptor specificity to human-like α2-6-linked sialosides with avidity comparable to wild-type H5 HA binding to avian-like α2-3-linked sialosides, and crystal structures revealed the structural basis for their preferential binding to human receptors.

Genes or proteins
hemagglutinin; HA
Receptors
α2-3-linked sialosides; α2-6-linked sialosides
Mechanism types
receptor_binding; cell_entry
Receptor Usage 1 records
Receptor Usage Extraction confidence 1.00
Key finding

Two H5N1 hemagglutinin mutants show structural evidence of shifted receptor binding specificity from avian-type α2-3-linked sialosides to human-type α2-6-linked sialosides.

Virus
IAV H5N1
Location
Not specified
Supporting text

Crystal structures of these two H5 HA mutants free and in complex with human and avian glycan receptor analogs reveal the structural basis for their preferential binding to human receptors.

Method
crystal structure; glycan array study
Receptors
sialosides