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Structure of key molecule in immune system provides clues for designing drugs
Date:12/27/2010

he complement protein C3 is enzymatically cleaved to form C3b, which binds to the surface of a target cell. C3b then binds factor B to produce C3bB. This complex, in turn, binds another enzyme, factor D (producing C3bBD), which cleaves the complex to form the active C3bBb. The major target of the active C3bBb is C3 itself, resulting in rapid amplification of the complement cascade.

To capture structural snapshots of C3bB and C3bBD, the researchers first generated mutant proteins that would stabilize the complexes in their active forms. Then, Lambris and Gros used x-ray crystallography to describe the two complexes in atomic detail. They found that, upon binding to C3b, factor B changes its shape to form an "open complex," which can then be bound by factor D. Factor D, in turn, shifts its shape in a more subtle yet no less important way: The free protein is inactive because a protein loop blocks the active site of the enzyme. Upon binding to C3bB, that loop alters its position, thereby activating factor D to cleave C3bB into the C3bBb complex.

These findings, Lambris said, provide molecular explanations for several safety features of the complement system. First, they explain why factor D is inactive on its own, but active when engaged by C3bB. They also illustrate a "double safety catch" mechanism the system uses to keep itself in check, preventing complement activation in the absence of a target.

Finally, and perhaps most importantly, they provide data that can aid the design of inhibitors against factor D, which may prove useful in the treatment of complement-associated diseases.

"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," Lamb
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

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