6Y54

Crystal structure of a Neisseria meningitidis serogroup A capsular oligosaccharide bound to a functional Fab

Summary for 6Y54

• Entry DOI: 10.2210/pdb6y54/pdb
• Descriptor: Fab A1.1 H chain, Fab A1.1 L chain, IODIDE ION, ... (8 entities in total)
• Functional Keywords: antigen-antibody complex, epitope mapping, carbohydrate, glycan, immune system
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 6
• Total formula weight: 150896.24

Authors

Dello Iacono, L.,Henriques, P.,Adamo, R. (deposition date: 2020-02-24, release date: 2020-10-07, Last modification date: 2024-10-09)

Primary citation

Henriques, P.,Dello Iacono, L.,Gimeno, A.,Biolchi, A.,Romano, M.R.,Arda, A.,Bernardes, G.J.L.,Jimenez-Barbero, J.,Berti, F.,Rappuoli, R.,Adamo, R.
Structure of a protective epitope reveals the importance of acetylation of Neisseria meningitidis serogroup A capsular polysaccharide.
Proc.Natl.Acad.Sci.USA, 117:29795-29802, 2020

PubMed Abstract: Meningococcal meningitis remains a substantial cause of mortality and morbidity worldwide. Until recently, countries in the African meningitis belt were susceptible to devastating outbreaks, largely attributed to serogroup A (MenA). Vaccination with glycoconjugates of MenA capsular polysaccharide led to an almost complete elimination of MenA clinical cases. To understand the molecular basis of vaccine-induced protection, we generated a panel of oligosaccharide fragments of different lengths and tested them with polyclonal and monoclonal antibodies by inhibition enzyme-linked immunosorbent assay, surface plasmon resonance, and competitive human serum bactericidal assay, which is a surrogate for protection. The epitope was shown to optimize between three and six repeating units and to be -acetylated. The molecular interactions between a protective monoclonal antibody and a MenA capsular polysaccharide fragment were further elucidated at the atomic level by saturation transfer difference NMR spectroscopy and X-ray crystallography. The epitope consists of a trisaccharide anchored to the antibody via the - and -acetyl moieties through either H-bonding or CH-π interactions. In silico docking showed that 3--acetylation of the upstream residue is essential for antibody binding, while -acetate could be equally accommodated at three and four positions of the other two residues. These results shed light on the mechanism of action of current MenA vaccines and provide a foundation for the rational design of improved therapies.

PubMed: 33158970
DOI: 10.1073/pnas.2011385117

Experimental method

X-RAY DIFFRACTION (2.67 Å)