Although relatively uncommon, meningitis — inflammation of the membranes covering the brain and spinal cord — can kill within hours. Immediately after infection, one major bacterial culprit — Neisseria meningitidis — coats itself with a human protein so that immune cells no longer recognize it as an intruder. Using X-ray crystallography, Susan Lea of the University of Oxford, UK, and her colleagues now describe the interaction between the microbe and the human protein.

Christoph Tang at Imperial College London had previously discovered that N. meningitidis uses a protein on its surface, dubbed factor-H-binding protein, to grasp hold of the human protein factor H. “Chris contacted us hoping that we could help to characterize these interactions further,” recalls Lea.

Factor H is part of the complement system, an arm of the immune system that attacks foreign bodies in the bloodstream. To prevent the system from targeting the body's own cells, factor H circulates in the bloodstream and binds to sugar molecules on human cells, flagging them as 'self'. N. meningitidis is one of several bacteria that have highjacked this mechanism by producing proteins that can also bind factor H.

Human factor H is a long molecule, made up of 20 domains strung together like beads on a string. Tang and Lea's groups determined that only two such 'beads' — numbers six and seven — are key to binding the bacterial protein. “This was good news because it meant we could look at the structure of just two domains,” says Lea.

But although the researchers had no trouble purifying and crystallizing the two factor-H domains in complex with the bacterial binding protein, solving the complex's structure proved tricky. “Some crystals are well behaved and some aren't. This one wasn't,” laughs Lea. Because the X-ray diffraction data were not of sufficient quality to deploy one of the two classical phasing methods, which use X-ray and computational information to resolve molecular structures, Lea and her colleagues had to find new ways to combine the information from both methods.

On page 890, the hard-earned structure reveals that the bacterial protein folds in the middle. Each half comprises a sheet of amino acids twisted into a barrel shape, with the human factor H portion stacked on top. “The structure essentially looks like two mugs side by side with a croissant on top,” says Lea.

Lea and her co-workers singled out two amino acids that seemed to be crucial to the two proteins' tight association. When they mutated the two amino acids, the bacterial protein no longer bound factor H. “Without the structural information we would have had to mutate every single amino acid in the protein to identify these two,” says Lea.

Meningitis is usually caused by viral or bacterial infection. For bacterial meningitis, the more severe form of the disease, there are vaccines for all but one type: meningitis B. Two candidate meningitis-B vaccines that are currently in clinical trials both use factor-H-binding protein as part of the vaccine formulation. However, this latest work suggests that the bacterial protein will immediately become bound by factor H and so will not generate an optimal immune response. “The mutated bacterial protein we have produced could make a better vaccine candidate,” Lea says, “because it doesn't bind factor H.”