 |
PDBsum entry 4ayd
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Immune system
|
PDB id
|
|
|
|
4ayd
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
123 a.a.
|
|
|
|
|
|
|
|
|
|
|
117 a.a.
|
|
|
|
|
|
|
|
|
|
|
238 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Design and evaluation of meningococcal vaccines through structure-Based modification of host and pathogen molecules.
|
|
|
Authors
|
|
S.Johnson,
L.Tan,
S.Van der veen,
J.Caesar,
E.Goicoechea de jorge,
R.J.Harding,
X.Bai,
R.M.Exley,
P.N.Ward,
N.Ruivo,
K.Trivedi,
E.Cumber,
R.Jones,
L.Newham,
D.Staunton,
R.Ufret-Vincenty,
R.Borrow,
M.C.Pickering,
S.M.Lea,
C.M.Tang.
|
|
|
Ref.
|
|
Plos Pathog, 2012,
8,
e1002981.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Neisseria meningitis remains a leading cause of sepsis and meningitis, and
vaccines are required to prevent infections by this important human pathogen.
Factor H binding protein (fHbp) is a key antigen that elicits protective
immunity against the meningococcus and recruits the host complement regulator,
fH. As the high affinity interaction between fHbp and fH could impair immune
responses, we sought to identify non-functional fHbps that could act as
effective immunogens. This was achieved by alanine substitution of fHbps from
all three variant groups (V1, V2 and V3 fHbp) of the protein; while some
residues affected fH binding in each variant group, the distribution of key
amino underlying the interaction with fH differed between the V1, V2 and V3
proteins. The atomic structure of V3 fHbp in complex with fH and of the
C-terminal barrel of V2 fHbp provide explanations to the differences in the
precise nature of their interactions with fH, and the instability of the V2
protein. To develop transgenic models to assess the efficacy of non-functional
fHbps, we determined the structural basis of the low level of interaction
between fHbp and murine fH; in addition to changes in amino acids in the fHbp
binding site, murine fH has a distinct conformation compared with the human
protein that would sterically inhibit binding to fHbp. Non-functional V1 fHbps
were further characterised by binding and structural studies, and shown in
non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and
precisely regulates complement system) to retain their immunogenicity. Our
findings provide a catalogue of non-functional fHbps from all variant groups
that can be included in new generation meningococcal vaccines, and establish
proof-in-principle for clinical studies to compare their efficacy with wild-type
fHbps.
|
|
|
|
|
|
|
