5C0S

Crystal structure of a generation 4 influenza hemagglutinin stabilized stem in complex with the broadly neutralizing antibody CR6261

Summary for 5C0S

• Entry DOI: 10.2210/pdb5c0s/pdb
• Related: 3GBM 3GBN 4EVN 5C0R
• Descriptor: Hemagglutinin, Envelope glycoprotein, Fibritin fusion protein, CR6261 antibody heavy chain, CR6261 antibody light chain (3 entities in total)
• Functional Keywords: hemagglutinin, immunogen, trimer, complex, viral protein-immune system complex, viral protein/immune system
• Biological source: Influenza A virus, Human immunodeficiency virus type 1 group M subtype B, Enterobacteria phage T4; More
• Total number of polymer chains: 3
• Total formula weight: 81450.67

Authors

Boyington, J.C.,Kwong, P.D.,Nabel, G.J.,Mascola, J.R. (deposition date: 2015-06-12, release date: 2015-09-02, Last modification date: 2024-11-20)

Primary citation

Yassine, H.M.,Boyington, J.C.,McTamney, P.M.,Wei, C.J.,Kanekiyo, M.,Kong, W.P.,Gallagher, J.R.,Wang, L.,Zhang, Y.,Joyce, M.G.,Lingwood, D.,Moin, S.M.,Andersen, H.,Okuno, Y.,Rao, S.S.,Harris, A.K.,Kwong, P.D.,Mascola, J.R.,Nabel, G.J.,Graham, B.S.
Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection.
Nat. Med., 21:1065-1070, 2015

PubMed Abstract: The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of influenza vaccines. In contrast, the immunogenically subdominant stem region of HA is highly conserved and recognized by antibodies capable of binding multiple HA subtypes. Here we report the structure-based development of an H1 HA stem-only immunogen that confers heterosubtypic protection in mice and ferrets. Six iterative cycles of structure-based design (Gen1-Gen6) yielded successive H1 HA stabilized-stem (HA-SS) immunogens that lack the immunodominant head domain. Antigenic characterization, determination of two HA-SS crystal structures in complex with stem-specific monoclonal antibodies and cryo-electron microscopy analysis of HA-SS on ferritin nanoparticles (H1-SS-np) confirmed the preservation of key structural elements. Vaccination of mice and ferrets with H1-SS-np elicited broadly cross-reactive antibodies that completely protected mice and partially protected ferrets against lethal heterosubtypic H5N1 influenza virus challenge despite the absence of detectable H5N1 neutralizing activity in vitro. Passive transfer of immunoglobulin from H1-SS-np-immunized mice to naive mice conferred protection against H5N1 challenge, indicating that vaccine-elicited HA stem-specific antibodies can protect against diverse group 1 influenza strains.

PubMed: 26301691
DOI: 10.1038/nm.3927

Experimental method

X-RAY DIFFRACTION (4.3 Å)