W0152

Structures of a Self-inhibitory Serine Protease and Its Pro-enzyme: Activation Mechanism of Complement Factor D. Hua Jing¹, Dwight Moore¹, Kevin J. Macon², Y. Sudhakara Babu³, Lawrence J. Delucas¹, John E. Volanakis², and Sthanam V. L. Narayana¹, ¹Center for Macromolecular Crystallography, University of Alabama at Birmingham, ²Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, ³BioCryst Pharmaceutical Inc., Birmingham, Alabama USA

Factor D is a complement serine protease essential for the activation of complement alternative pathway. Factor D displays a typical trypsin-like fold, but the active site residues adopt an atypical conformation. Crystal structures of native factor D in two crystal forms and in complex with three different inhibitors have been solved at resolutions ranging from 2.3Å to 1.5Å. These structures showed that the atypical active site conformation is due to the presence of a self-inhibitory loop which overlaps with the binding positions of many peptidomimetic inhibitors in other serine protease complexes. Recently, the structure of pro-factor D has been solved at 2.1Å resolution in a P2₁ crystal form containing four molecules in the asymmetric unit. Pro-factor D displays an active catalytic triad conformation, flipped conformation for the self-inhibitory loop, and similar conformation for the flexible activation domain as that in trypsinogen, chymotrypsinogen, and prethrombin-2. Comparison between the structure of pro-enzyme and mature enzyme revealed the activation mechanism of complement factor D.