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As a central component of C3 convertase, C3b forms an enzyme complex that cleaves its parent molecule C3, which leads to the generation and deposition of more C3b on the bacterial surface. The structure of C3 convertase provides important details about the molecular mechanisms behind these activation and amplification processes. When SCIN is bound to C3 convertase, the enzyme can no longer generate C3b and amplify the complement response, which likely renders the immune system less effective against staphylococcal infections.

"We plan to look for potential drugs that mimic the interaction of SCIN and C3 convertase and inhibit complement without triggering an adverse immune response," says Lambris. The crystals were therefore examined for critical interaction points between the SCIN inhibitor and C3 convertase.

The second study, describing the structure formed between C3b and factor H, a key regulator of the complement system, is important because of its suspected involvement in a number of immune-related diseases. "It was a surprise to see that the factor H fragment is spread across the entire C3b complex," notes Lambris.

Factor H binding inhibits C3 convertase activity and prevents the complement response from attacking the host's own cells. "This gives us a structural model for designing new therapies for several immune-mediated diseases," said Lambris.

Mutations in factor H are associated with age-related macular degeneration, the major cause of blindness in elderly people in the U.S; atypical hemolytic uremic syndrome, a rare but severe kidney disease that causes acute renal failure and high blood pressure; and membranoproliferative glomerulonephritis type II, another rare, progressive renal disor
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