Abstract
Neisserial heparin-binding antigen (NHBA) is a surface-exposed lipoprotein from Neisseria meningitidis and is a component of the meningococcus B vaccine Bexsero. As part of a study to characterize the three-dimensional structure of NHBA and the molecular basis of the human immune response to Bexsero, the crystal structures of two fragment antigen-binding domains (Fabs) isolated from human monoclonal antibodies targeting NHBA were determined. Through a high-resolution analysis of the organization and the amino-acid composition of the CDRs, these structures provide broad insights into the NHBA epitopes recognized by the human immune system. As expected, these Fabs also show remarkable structural conservation, as shown by a structural comparison of 15 structures of apo Fab 10C3 which were obtained from crystals grown in different crystallization conditions and were solved while searching for a complex with a bound NHBA fragment or epitope peptide. This study also provides indirect evidence for the intrinsically disordered nature of two N-terminal regions of NHBA.
Highlights
Serogroup B Neisseria meningitidis (MenB) is a Gramnegative encapsulated bacterium that can cause invasive meningococcal disease, which is characterized by severe infection and fatal sepsis (Rosenstein et al, 2001)
neisserial heparin-binding antigen (NHBA) is a lipoprotein that is specific to Neisseria species, and its gene is ubiquitous in all meningococcal group B strains (Bambini et al, 2009; Jacobsson et al, 2006; Lucidarme et al, 2010; Muzzi et al, 2013)
Gene-sequence analysis from genetically diverse group B strains revealed the existence of more than 600 NHBA variants, termed peptides (Muzzi et al, 2013; Bambini et al, 2013). Examination of these gene sequences revealed the presence of variable segments of NHBA at the level of the amino-acid sequence, with the highest sequence diversity clustered in the N-terminal region of the protein
Summary
Serogroup B Neisseria meningitidis (MenB) is a Gramnegative encapsulated bacterium that can cause invasive meningococcal disease, which is characterized by severe infection and fatal sepsis (Rosenstein et al, 2001). Gene-sequence analysis from genetically diverse group B strains revealed the existence of more than 600 NHBA variants, termed peptides (Muzzi et al, 2013; Bambini et al, 2013). Examination of these gene sequences revealed the presence of variable segments of NHBA at the level of the amino-acid sequence, with the highest sequence diversity clustered in the N-terminal region of the protein (approximately residues 1–240). The structure of the Nterminal domain remains unknown, and secondary-structure predictions suggest that it is highly flexible and contains intrinsically disordered regions (Esposito et al, 2011; Supplementary Fig. S1b)
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