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Structural basis of profactor D activation: from a highly flexible zymogen to a novel self-inhibited serine protease, complement factor D.
- Source :
-
The EMBO journal [EMBO J] 1999 Feb 15; Vol. 18 (4), pp. 804-14. - Publication Year :
- 1999
-
Abstract
- The crystal structure of profactor D, determined at 2.1 A 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.
- Subjects :
- Amino Acid Sequence
Binding Sites
Crystallography, X-Ray
Enzyme Activation
Humans
Models, Molecular
Molecular Sequence Data
Protein Conformation
Protein Processing, Post-Translational
Protein Structure, Secondary
Recombinant Proteins chemistry
Sequence Homology, Amino Acid
Complement Factor D chemistry
Enzyme Precursors chemistry
Protein Precursors chemistry
Serine Endopeptidases chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0261-4189
- Volume :
- 18
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The EMBO journal
- Publication Type :
- Academic Journal
- Accession number :
- 10022823
- Full Text :
- https://doi.org/10.1093/emboj/18.4.804