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Structural Basis for the Immunogenic Properties of the Meningococcal Vaccine Candidate LP2086*S⃞

By Alessandro Mascioni, Breagh E. Bentley, Rosaria Camarda, Deborah A. Dilts, Pamela Fink, Viktoria Gusarova, Susan K. Hoiseth, Jaison Jacob, Shuo L. Lin, Karl Malakian, Lisa K. McNeil, Terri Mininni, Franklin Moy, Ellen Murphy, Elena Novikova, Scott Sigethy, Yingxia Wen, Gary W. Zlotnick and Désirée H. H. Tsao

Abstract

LP2086 is a family of outer membrane lipoproteins from Neisseria meningitidis, which elicits bactericidal antibodies and are currently undergoing human clinical trials in a bivalent formulation where each antigen represents one of the two known LP2086 subfamilies. Here we report the NMR structure of the recombinant LP2086 variant B01, a representative of the LP2086 subfamily B. The structure reveals a novel fold composed of two domains: a “taco-shaped” N-terminal β-sheet and a C-terminal β-barrel connected by a linker. The structure in micellar solution is consistent with a model of LP2086 anchored to the outer membrane bilayer through its lipidated N terminus. A long flexible chain connects the folded part of the protein to the lipid anchor and acts as spacer, making both domains accessible to the host immune system. Antibodies broadly reactive against members from both subfamilies have been mapped to the N terminus. A surface of subfamily-defining residues was identified on one face of the protein, offering an explanation for the induction of subfamily-specific bactericidal antibodies

Topics: Protein Structure and Folding
Publisher: American Society for Biochemistry and Molecular Biology
OAI identifier: oai:pubmedcentral.nih.gov:2659232
Provided by: PubMed Central
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