7lcv

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Factor H enhancing human antibody fragment (Fab) to meningococcal Factor H binding protein

Structural highlights

7lcv is a 3 chain structure with sequence from Homo sapiens and Neisseria meningitidis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.7Å
Ligands:CL
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FHBP_NEIMB A bacterial surface lipoprotein that binds host (human) complement factor H (fH, gene CFH), binding contributes to the avoidance of complement-mediated lysis by N.meningitidis. Binding of fH to the bacteria surface is independent of bacterial sialic acid moieties (PubMed:16751403). fH binding affinity is high enough that it may sequester plasma fH, depleting its circulating levels and de-regulating complement in the host (Probable). This protein induces high levels of bactericidal antibodies in mice (PubMed:12642606, PubMed:15039331, PubMed:15664958, PubMed:21753121, PubMed:23133374).[1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

Microbial pathogens bind host complement regulatory proteins to evade the immune system. The bacterial pathogen Neisseria meningitidis, or meningococcus, binds several complement regulators, including human Factor H (FH). FH binding protein (FHbp) is a component of two licensed meningococcal vaccines and in mice FHbp elicits antibodies that inhibit binding of FH to FHbp, which defeat the bacterial evasion mechanism. However, humans vaccinated with FHbp develop antibodies that enhance binding of FH to the bacteria, which could limit the effectiveness of the vaccines. In the present study, we show that two vaccine-elicited antibody fragments (Fabs) isolated from different human subjects increase binding of complement FH to meningococcal FHbp by ELISA. The two Fabs have different effects on the kinetics of FH binding to immobilized FHbp as measured by surface plasmon resonance. The 1.7- and 2.0-A resolution X-ray crystal structures of the Fabs in complexes with FHbp illustrate that the two Fabs bind to similar epitopes on the amino-terminal domain of FHbp, adjacent to the FH binding site. Superposition models of ternary complexes of each Fab with FHbp and FH show that there is likely minimal contact between the Fabs and FH. Collectively, the structures reveal that the Fabs enhance binding of FH to FHbp by altering the conformations and mobilities of two loops adjacent to the FH binding site of FHbp. In addition, the 1.5 A-resolution structure of one of the isolated Fabs defines the structural rearrangements associated with binding to FHbp. The FH-enhancing human Fabs, which are mirrored in the human polyclonal antibody responses, have important implications for tuning the effectiveness of FHbp-based vaccines.

Two human antibodies to a meningococcal serogroup B vaccine antigen enhance binding of complement Factor H by stabilizing the Factor H binding site.,Sands NA, Beernink PT PLoS Pathog. 2021 Jun 14;17(6):e1009655. doi: 10.1371/journal.ppat.1009655. , eCollection 2021 Jun. PMID:34125873[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Masignani V, Comanducci M, Giuliani MM, Bambini S, Adu-Bobie J, Arico B, Brunelli B, Pieri A, Santini L, Savino S, Serruto D, Litt D, Kroll S, Welsch JA, Granoff DM, Rappuoli R, Pizza M. Vaccination against Neisseria meningitidis using three variants of the lipoprotein GNA1870. J Exp Med. 2003 Mar 17;197(6):789-99. PMID:12642606 doi:10.1084/jem.20021911
  2. ↑ Fletcher LD, Bernfield L, Barniak V, Farley JE, Howell A, Knauf M, Ooi P, Smith RP, Weise P, Wetherell M, Xie X, Zagursky R, Zhang Y, Zlotnick GW. Vaccine potential of the Neisseria meningitidis 2086 lipoprotein. Infect Immun. 2004 Apr;72(4):2088-100. PMID:15039331 doi:10.1128/IAI.72.4.2088-2100.2004
  3. ↑ Giuliani MM, Santini L, Brunelli B, Biolchi A, Aricò B, Di Marcello F, Cartocci E, Comanducci M, Masignani V, Lozzi L, Savino S, Scarselli M, Rappuoli R, Pizza M. The region comprising amino acids 100 to 255 of Neisseria meningitidis lipoprotein GNA 1870 elicits bactericidal antibodies. Infect Immun. 2005 Feb;73(2):1151-60. PMID:15664958 doi:10.1128/IAI.73.2.1151-1160.2005
  4. ↑ Schneider MC, Exley RM, Chan H, Feavers I, Kang YH, Sim RB, Tang CM. Functional significance of factor H binding to Neisseria meningitidis. J Immunol. 2006 Jun 15;176(12):7566-75. PMID:16751403 doi:10.4049/jimmunol.176.12.7566
  5. ↑ Scarselli M, Arico B, Brunelli B, Savino S, Di Marcello F, Palumbo E, Veggi D, Ciucchi L, Cartocci E, Bottomley MJ, Malito E, Lo Surdo P, Comanducci M, Giuliani MM, Cantini F, Dragonetti S, Colaprico A, Doro F, Giannetti P, Pallaoro M, Brogioni B, Tontini M, Hilleringmann M, Nardi-Dei V, Banci L, Pizza M, Rappuoli R. Rational design of a meningococcal antigen inducing broad protective immunity. Sci Transl Med. 2011 Jul 13;3(91):91ra62. PMID:21753121 doi:10.1126/scitranslmed.3002234
  6. ↑ Johnson S, Tan L, van der Veen S, Caesar J, Goicoechea De Jorge E, Harding RJ, Bai X, Exley RM, Ward PN, Ruivo N, Trivedi K, Cumber E, Jones R, Newham L, Staunton D, Ufret-Vincenty R, Borrow R, Pickering MC, Lea SM, Tang CM. Design and Evaluation of Meningococcal Vaccines through Structure-Based Modification of Host and Pathogen Molecules. PLoS Pathog. 2012 Oct;8(10):e1002981. doi: 10.1371/journal.ppat.1002981. Epub, 2012 Oct 25. PMID:23133374 doi:http://dx.doi.org/10.1371/journal.ppat.1002981
  7. ↑ Schneider MC, Prosser BE, Caesar JJ, Kugelberg E, Li S, Zhang Q, Quoraishi S, Lovett JE, Deane JE, Sim RB, Roversi P, Johnson S, Tang CM, Lea SM. Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates. Nature. 2009 Apr 16;458(7240):890-3. Epub 2009 Feb 18. PMID:19225461 doi:10.1038/nature07769
  8. ↑ Sands NA, Beernink PT. Two human antibodies to a meningococcal serogroup B vaccine antigen enhance binding of complement Factor H by stabilizing the Factor H binding site. PLoS Pathog. 2021 Jun 14;17(6):e1009655. PMID:34125873 doi:10.1371/journal.ppat.1009655

Contents


PDB ID 7lcv

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