title: Structural Basis for a Switch in Receptor Binding Specificity of Two H5N1 Hemagglutinin Mutants.
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.
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Xueyong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Karthik
authors.initials: K
authors.lastname: Viswanathan
authors.affiliation: 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.
authors.forename: Rahul
authors.initials: R
authors.lastname: Raman
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Wenli
authors.initials: W
authors.lastname: Yu
authors.affiliation: 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: rams@mit.edu.
authors.forename: Ram
authors.initials: R
authors.lastname: Sasisekharan
authors.affiliation: 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: wilson@scripps.edu.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001717:Birds / Q000378:metabolism; D018360:Crystallography, X-Ray / Q000379:methods; D006388:Hemagglutinins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D006388:Hemagglutinins; D011134:Polysaccharides; D011956:Receptors, Cell Surface
keywords: H5N1 influenza virus; crystal structure; glycan complex; hemagglutinin; receptor binding specificity; transmission