7SEM

Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins

Summary for 7SEM

• Entry DOI: 10.2210/pdb7sem/pdb
• Descriptor: MPE8 Fab heavy chain, Fusion glycoprotein F0, MPE8 Fab light chain, ... (5 entities in total)
• Functional Keywords: human metapneumovirus, fusion protein, viral protein, viral protein-immune system complex, viral protein/immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 107779.10

Authors

Rush, S.A.,Hsieh, C.-L.,McLellan, J.S. (deposition date: 2021-09-30, release date: 2022-02-16, Last modification date: 2024-11-20)

Primary citation

Hsieh, C.L.,Rush, S.A.,Palomo, C.,Chou, C.W.,Pickens, W.,Mas, V.,McLellan, J.S.
Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins.
Nat Commun, 13:1299-1299, 2022

PubMed Abstract: The human metapneumovirus (hMPV) fusion (F) protein is essential for viral entry and is a key target of neutralizing antibodies and vaccine development. The prefusion conformation is thought to be the optimal vaccine antigen, but previously described prefusion F proteins expressed poorly and were not well stabilized. Here, we use structures of hMPV F to guide the design of 42 variants containing stabilizing substitutions. Through combinatorial addition of disulfide bonds, cavity-filling substitutions, and improved electrostatic interactions, we describe a prefusion-stabilized F protein (DS-CavEs2) that expresses at 15 mg/L and has a melting temperature of 71.9 °C. Crystal structures of two prefusion-stabilized hMPV F variants reveal that antigenic surfaces are largely unperturbed. Importantly, immunization of mice with DS-CavEs2 elicits significantly higher neutralizing antibody titers against hMPV A1 and B1 viruses than postfusion F. The improved properties of DS-CavEs2 will advance the development of hMPV vaccines and the isolation of therapeutic antibodies.

PubMed: 35288548
DOI: 10.1038/s41467-022-28931-3

Experimental method

X-RAY DIFFRACTION (2.2 Å)