X-Ray Crystallography Study Reveals Complement Proteins Interactions

In the central complement-amplification step, a complex consisting of surface-bound C3b and factor B is cleaved by factor D to generate active convertases on targeted surfaces. Malfunction of this mechanism has been implicated in at least 30 diseases, including stroke, myocardial infarction, and age-related macular degeneration.

In the current study, investigators at the University of Pennsylvania School of Medicine (Philadelphia, USA) and Utrecht University (The Netherlands) generated stable, mutant forms of the protein complex composed of surface-bound C3b, factor B, and factor D. They then examined crystals of the protein complex by X-ray crystallography.

In the December 24, 2010, issue of the journal Science the investigators presented crystal structures of the pro-convertase C3bB at four angstrom resolution and its complex with factor D at three and a half angstrom resolution. There data showed how factor B binding to C3b formed an open "activation” state of C3bB. Factor D specifically bound to the open conformation of factor B through a site distant from the catalytic center and was activated by the substrate, which displaced factor D's self-inhibitory loop. This concerted proteolytic mechanism, which was cofactor-dependent and substrate-induced, restricts complement amplification to C3b-tagged target cells.

"Besides shedding light on a highly elegant mechanism of concerted activation and intrinsic regulation, this work also offers a detailed insight into one of the most important therapeutic targets within the complement network, which may facilitate rational drug development and could lead to novel drugs for treating complement-related diseases," said senior author Dr. John Lambris, professor of research medicine at the University of Pennsylvania School of Medicine. "Now we will be able to design specific complement inhibitors to target this complex and in that way inhibit activation of the complement cascade, because now we know which parts of the proteins are essential for activity.”

Related Links:
University of Pennsylvania School of Medicine
Utrecht University