BACTERICIDAL ANTIBODY RECOGNITION OF A PORA EPITOPE OF NEISSERIA-MENINGITIDIS - CRYSTAL-STRUCTURE OF A FAB FRAGMENT IN COMPLEX WITH A FLUORESCEIN-CONJUGATED PEPTIDE
Jmh. Vandenelsen et al., BACTERICIDAL ANTIBODY RECOGNITION OF A PORA EPITOPE OF NEISSERIA-MENINGITIDIS - CRYSTAL-STRUCTURE OF A FAB FRAGMENT IN COMPLEX WITH A FLUORESCEIN-CONJUGATED PEPTIDE, Proteins, 29(1), 1997, pp. 113-125
Class 1 outer membrane protein PorA of Neisseria meningitidis is a vac
cine candidate against bacterial meningitis, Antibodies against PorA a
re able to induce complement-mediated bacterial killing and thereby pl
ay an important role in protection against meningococcal disease, Bact
ericidal antibodies are all directed against variable regions VR1 and
VR2 of the PorA sequence, corresponding to loops 1 and 4 of a two-dime
nsional topology model of the porin with eight extracellular loops, We
have determined the crystal structure to 2.6 Angstrom resolution of t
he Fab fragment of bactericidal antibody MN12H2 against meningococcal
PorA in complex with a linear fluorescein-conjugated peptide TKDTNNNL
derived from the VR2 sequence of sero-subtype P1.7,16 (residues 180-18
7) from meningococcal strain H44/76, The peptide folds deeply into the
binding cavity of the Fab molecule in a type I beta-turn, with the mi
nimal P1.16 epitope DTNNN virtually completely buried, The structure r
eveals II-bonds and van der Waals interactions with all minimal epitop
e residues and one essential salt bridge between Asp-182 of the peptid
e and His-31 of the MN12H2 light chain, The key components of the reco
gnition of PorA epitope P1.16 by bactericidal antibody MN12H2 correspo
nd well with available thermodynamic data from binding studies, Furthe
rmore, they indicate the structural basis of an increased endemic inci
dence of infection by group B meningococci in England and Wales since
1981 associated with the occurrence of an Neisseria meningitidis escap
e mutant (strain MC58), The observed three-dimensional conformation of
the peptide provides a rationale for the development of a synthetic p
eptide vaccine against meningococcal disease. (C) 1997 Wiley-Liss, Inc
.