Structure of a zoonotic H5N1 hemagglutinin reveals a receptor-binding site occupied by an auto-glycan.

Nicholas C Morano^1,2,3 Yicheng Guo⁴ Jordan E Becker^1,2,3 Zhiteng Li⁵ Jian Yu⁵ David D Ho⁵ Lawrence Shapiro^1,2,6 Peter D Kwong^1,7

Affiliations 7 institutions

Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027, USA.
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: [email protected].
Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027, USA. Electronic address: [email protected].
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10027, USA. Electronic address: [email protected].

PMID39884273 DOI10.1016/j.str.2025.01.001 Year2025 Journal Structure (London, England : 1993) Structure Languageeng Statusppublish

Abstract

Highly pathogenic avian influenza has spilled into many mammals, most notably cows and poultry, with several dozen human breakthrough infections. Zoonotic crossovers, with hemagglutinins mutated to enhance viral ability to use human α2-6-linked sialic acid receptors versus avian α2-3-linked ones, highlight the pandemic risk. To gain insight into these crossovers, we determined the cryoelectron microscopy (cryo-EM) structure of the hemagglutinin from the zoonotic H5N1 A/Texas/37/2024 strain (clade 2.3.4.4b) in complex with a previously reported neutralizing antibody. Surprisingly, we found that the receptor-binding site of this H5N1 hemagglutinin was already occupied by an α2-3-linked sialic acid and that this glycan emanated from asparagine N169 of a neighboring protomer on hemagglutinin itself. This structure thus highlights recognition by influenza hemagglutinin of an "auto"-α2-3-linked sialic acid from N169, an N-linked glycan conserved in 95% of H5 strains, and adds "auto-glycan recognition," which may play a role in viral dispersal, to the complexities surrounding H5N1 zoonosis.

Supporting text Virus Host Location

auto-binding 1 clade 2.3.4.4b 19 cryo-EM 7 glycan shielding 1 hemagglutinin 31 influenza A virus 227 N-linked glycan 2 sialic acid 12 viral dispersal 1 zoonosis 116 Hemagglutinin Glycoproteins, Influenza Virus 180 Influenza A Virus, H5N1 Subtype 300 Polysaccharides 31 Animals 1948 Antibodies, Neutralizing 80 Binding Sites 89 Cryoelectron Microscopy 37 Humans 1440 Influenza, Human 286 Models, Molecular 99 N-Acetylneuraminic Acid 25 Protein Binding 193 Receptors, Virus 204

Evidence records

1 total

Functional Mechanism

1 records · 1 evidence types

Evidence type Receptor Usage

1 records

OVE8871 Receptor Usage

Key finding

Highly pathogenic avian influenza, specifically the H5N1 subtype, has spilled over from poultry and cows into humans, resulting in several dozen human infections.

Virus