4AYM

Structure of a complex between CCPs 6 and 7 of Human Complement Factor H and Neisseria meningitidis FHbp Variant 3 P106A mutant

Summary for 4AYM

• Entry DOI: 10.2210/pdb4aym/pdb
• Related: 1FHC 1HAQ 1HCC 1HFH 1HFI 1KOV 2G7I 2JGW 2JGX 2UWN 2V8E 2W80 2W81 2WII 2XQW 4AYD 4AYE 4AYI 4AYN
• Descriptor: COMPLEMENT FACTOR H, FACTOR H BINDING PROTEIN (3 entities in total)
• Functional Keywords: immune system, antigens, vaccines
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Secreted: P08603
• Total number of polymer chains: 6
• Total formula weight: 116616.71

Authors

Johnson, S.,Tan, L.,van der Veen, S.,Caesar, J.,Goicoechea De Jorge, E.,Everett, R.J.,Bai, X.,Exley, R.M.,Ward, P.N.,Ruivo, N.,Trivedi, K.,Cumber, E.,Jones, R.,Newham, L.,Staunton, D.,Borrow, R.,Pickering, M.,Lea, S.M.,Tang, C.M. (deposition date: 2012-06-21, release date: 2012-11-07, Last modification date: 2024-10-16)

Primary citation

Johnson, S.,Tan, L.,Van Der Veen, S.,Caesar, J.,Goicoechea De Jorge, E.,Harding, R.J.,Bai, X.,Exley, R.M.,Ward, P.N.,Ruivo, N.,Trivedi, K.,Cumber, E.,Jones, R.,Newham, L.,Staunton, D.,Ufret-Vincenty, R.,Borrow, R.,Pickering, M.C.,Lea, S.M.,Tang, C.M.
Design and Evaluation of Meningococcal Vaccines Through Structure-Based Modification of Host and Pathogen Molecules.
Plos Pathog., 8:2981-, 2012

PubMed 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.

PubMed: 23133374
DOI: 10.1371/JOURNAL.PPAT.1002981

Experimental method

X-RAY DIFFRACTION (3 Å)