3QWO

Crystal structure of a motavizumab epitope-scaffold bound to motavizumab Fab

Summary for 3QWO

• Entry DOI: 10.2210/pdb3qwo/pdb
• Related: 3IXT
• Descriptor: motavizumab light chain, motavizumab heavy chain, motavizumab epitope scaffold, ... (6 entities in total)
• Functional Keywords: immune complex, immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 6
• Total formula weight: 107854.06

Authors

McLellan, J.S.,Kwong, P.D. (deposition date: 2011-02-28, release date: 2011-05-04, Last modification date: 2024-11-06)

Primary citation

McLellan, J.S.,Correia, B.E.,Chen, M.,Yang, Y.,Graham, B.S.,Schief, W.R.,Kwong, P.D.
Design and characterization of epitope-scaffold immunogens that present the motavizumab epitope from respiratory syncytial virus.
J.Mol.Biol., 409:853-866, 2011

PubMed Abstract: Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, but an effective vaccine has not yet been developed. An ideal vaccine would elicit protective antibodies while avoiding virus-specific T-cell responses, which have been implicated in vaccine-enhanced disease with previous RSV vaccines. We propose that heterologous proteins designed to present RSV-neutralizing antibody epitopes and to elicit cognate antibodies have the potential to fulfill these vaccine requirements, as they can be fashioned to be free of viral T-cell epitopes. Here we present the design and characterization of three epitope-scaffolds that present the epitope of motavizumab, a potent neutralizing antibody that binds to a helix-loop-helix motif in the RSV fusion glycoprotein. Two of the epitope-scaffolds could be purified, and one epitope-scaffold based on a Staphylococcus aureus protein A domain bound motavizumab with kinetic and thermodynamic properties consistent with the free epitope-scaffold being stabilized in a conformation that closely resembled the motavizumab-bound state. This epitope-scaffold was well folded as assessed by circular dichroism and isothermal titration calorimetry, and its crystal structure (determined in complex with motavizumab to 1.9 Å resolution) was similar to the computationally designed model, with all hydrogen-bond interactions critical for binding to motavizumab preserved. Immunization of mice with this epitope-scaffold failed to elicit neutralizing antibodies but did elicit sera with F binding activity. The elicitation of F binding antibodies suggests that some of the design criteria for eliciting protective antibodies without virus-specific T-cell responses are being met, but additional optimization of these novel immunogens is required.

PubMed: 21549714
DOI: 10.1016/j.jmb.2011.04.044

Experimental method

X-RAY DIFFRACTION (1.9 Å)