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  • The EMBO Journal (1999) 18, 804 - 814
  • doi:10.1093/emboj/18.4.804

Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D

Hua Jing1, Kevin J. Macon2, Dwight Moore1, Lawrence J. DeLucas1, John E. Volanakis2,3 and Sthanam V.L. Narayana1

  1. Center for Macromolecular Crystallography, University of Alabama at Birmingham, Birmingham, AL 35294, USA
  2. Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
  3. Present address: Biomedical Science Research Center 'A.Fleming', 166 72 Vari, Greece

Correspondence to:

Sthanam V.L. Narayana, E-mail: narayana@pearl.cmc.uab.edu

Received 12 October 1998; Accepted 9 December 1998; Revised 7 December 1998

The crystal structure of profactor D, determined at 2.1 Å resolution with an Rfree and an R-factor of 25.1 and 20.4%, respectively, displays highly flexible or disordered conformation for five regions: N-22, 71–76, 143–152, 187–193 and 215–223. A comparison with the structure of its mature serine protease, complement factor D, revealed major conformational changes in the similar regions. Comparisons with the zymogen–active enzyme pairs of chymotrypsinogen, trypsinogen and prethrombin-2 showed a similar distribution of the flexible regions. However, profactor D is the most flexible of the four, and its mature enzyme displays inactive, self-inhibited active site conformation. Examination of the surface properties of the N-terminus-binding pocket indicates that Ile16 may play the initial positioning role for the N-terminus, and Leu17 probably also helps in inducing the required conformational changes. This process, perhaps shared by most chymotrypsinogen-like zymogens, is followed by a factor D-unique step, the re-orientation of an external Arg218 to an internal position for salt-bridging with Asp189, leading to the generation of the self-inhibited factor D.

  • Keywords:

    • conformational change,
    • crystal structure,
    • factor D,
    • serine protease,
    • zymogen activation