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 Wilson^4,5

Affiliations 5 institutions

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
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.
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].
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].

PMID26586437 DOI10.1016/j.celrep.2015.10.027 Year2015 Journal Cell reports Cell Rep Languageeng Statusppublish

Abstract

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.

Supporting text Virus Host Location

crystal structure 4 glycan complex 1 H5N1 influenza virus 4 hemagglutinin 31 receptor binding specificity 4 transmission 55 Animals 1948 Birds 212 Crystallography, X-Ray 32 Hemagglutinins 24 Humans 1440 Influenza A Virus, H5N1 Subtype 300 Mutation 209 Polysaccharides 31 Protein Binding 193 Receptors, Cell Surface 28

Evidence records

2 total

Functional Mechanism

2 records · 2 evidence types

Evidence type Receptor Usage

1 records

OVE2233 Receptor Usage

Key finding

Crystal structures show that H5N1 influenza virus HA mutants preferentially bind human-like α2‑6‑linked sialoside receptors rather than avian‑like α2‑3‑linked receptors.

Virus

Host

Location

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 analysis | structural complex determination
Receptors: human-like α2-6-linked sialosides | avian-like α2-3-linked sialosides

Evidence type Molecular Adaptation

1 records

OVE2234 Molecular Adaptation

Key finding

Two H5N1 hemagglutinin (HA) mutants exhibited a molecular adaptation that switched receptor specificity from avian-like α2-3-linked sialosides to human-like α2-6-linked sialosides with comparable binding avidity.

Virus

Host

Location

Supporting text

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.

Genes or proteins: hemagglutinin (HA)
Receptors: α2-6-linked sialosides | α2-3-linked sialosides
Mutations: two HA mutants (not specified by position in text)
Mechanism types: receptor binding | host-range expansion

References

32 references

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