Structural Biology of Influenza Hemagglutinin: An Amaranthine Adventure

Abstract

Hemagglutinin (HA) glycoprotein is an important focus of influenza research due to its role in antigenic drift and shift, as well as its receptor binding and membrane fusion functions, which are indispensable for viral entry. Over the past four decades, X-ray crystallography has greatly facilitated our understanding of HA receptor binding, membrane fusion, and antigenicity. The recent advances in cryo-EM have further deepened our comprehension of HA biology. Since influenza HA constantly evolves in natural circulating strains, there are always new questions to be answered. The incessant accumulation of knowledge on the structural biology of HA over several decades has also facilitated the design and development of novel therapeutics and vaccines. This review describes the current status of the field of HA structural biology, how we got here, and what the next steps might be.

Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses

“…In the crystal structures of the avian H5 HA and canine H3 HA complexed with avian-type receptor glycans 6-Su-3'SLN and 6-Su-SLe x , the side chain of K193 interacts with the sulfogroup attached to GlcNAc-3 (Collins et al, 2014;Xiong et al, 2013). In the H3N2/1968 HA complexes with human-type receptor analogues LSTc and 6SLN-LN, the side chain of S193 contacts the Gal-4 residue of the glycan (Eisen et al, 1997;Wu and Wilson, 2020). These observations suggest that substitution N193S affects binding avidity of HK by altering HA interactions with sub-terminal saccharide residues of both avian-type and human-type receptor glycans.…”

Antibody Focusing to Conserved Sites of Vulnerability: The Immunological Pathways for ‘Universal’ Influenza Vaccines

“…The viral spike glycoprotein hemagglutinin currently serves as the primary seasonal influenza vaccine antigen, but also bears a number of conserved features which have been proposed as broadly protective ‘universal’ vaccine targets [ 1 , 4 , 31 , 34 , 35 , 94 , 95 ]. HA is a homotrimer consisting of a highly variable globular head domain (HA1 subunit) and a more conserved membrane proximal stalk region (HA2 subunit) [ 94 , 96 , 97 , 98 ]. Structurally resolved sites of vulnerability are described in detail below and include targets on both the head and stalk domains ( Figure 3 ).…”

50 Years of structural immunology

“…The next advance in 1988 was the structure of HA in complex with its receptor; the sialic acid receptor could then be visualized binding in a shallow receptor binding pocket at the apex of the HA trimer (PDB IDs: 5HMG, 4HMG) (128). Much of the history of influenza HA structural studies can be found in (129) and a recent update this year in (130).…”