Bactericidal antibody recognition of meningococcal PorA by induced fit - Comparison of liganded and unliganded Fab structures

MN12H2 is a bactericidal antibody directed against outer membrane protein P orA epitope P1.16 of Neisseria meningitidis. Binding of MN12H2 to PorA at t he meningococcal surface activates the classical complement pathway resulti ng in bacterial lysis, We have deter mined the crystal structure of the unl iganded MN12H2 Fab fragment in two different crystal forms and compared it with the structure of the Fab in complex with a P1.16-derived peptide. The unliganded Fabs have elbow bend angles of 155 degrees and 159 degrees, wher eas the liganded Fab has a more closed elbow bend of 143 degrees, Substanti al differences in quaternary and tertiary structure of the antigen binding site are observed between the unliganded and liganded MN12H2 Fab structures that can be attributed to peptide binding. The variable light and heavy ch ain interface of the liganded Fab is twisted by a 5 degrees rotation along an axis approximately perpendicular to the plane of the interface. Hypervar iable loops H1, H2, and framework loop FR-HS follow this rotation. The hype rvariable loop H3 undergoes conformational changes but remains closely link ed to hypervariable loop L1. In Fab-peptide structures, the MN12H2 binding site is narrowed upon peptide binding due to the formation of a "false floo r" mediated by arginine residue 101 of the light chain. These results indic ate that PorA epitope P1.16 of N. meningitidis is recognized by the complem ent-activating antibody MN12H2 through induced fit, allowing the formation of a highly complementary immune complex.