Title : The crystal
structure of PR3 , a neutrophil
serine proteinase antigen of Wegener's granulomatosis antibodies
Abstract :
- The crystal structure of PR3 , a serine proteinase from the azurophilic granules of human polymorphonuclear neutrophils, has been solved by molecular replacement using the human leukocyte elastase structure
- The PR3 structure has been refined to an R-factor (= sigma parallel Fo magnitude of-Fc parallel/sigma magnitude of Fo) of 0.201 for all data in the range of 10.0 to 2.2 A resolution
- The enzyme was crystallized in space group P21 with four molecules in the asymmetric unit (Vm approximately equal to 2.6 A/Da)
- The overall fold consists of two domains of beta-barrel structures typical of the chymotrypsin family of serine proteinases
- In general, the substrate binding sites , S4 to S3', are more polar than comparable sites in the related proteinase , human leukocyte elastase
- The experimentally observed preference of PR3 for small aliphatic residues residues at the P1 position of a substrate is explained by the Val to Ile substitution at position 190 when compared to the elastase structure
- The substitution of Ala by Asp at position 213 at the back of S1 should not affect its specificity greatly, as the Asp side-chain points back into the interior of the protein
- The PR3 structure includes a disaccharide unit (N-linked 2-acetamido-2-deoxy-beta-D-glucopyranose and 1,6-linked alpha-L-fucopyranose) covalently attached to Asn 159
- The linear antigenic sites of PR3 reported to react with Wegener's granulomatosis autoantibodies occur in regions of the three-dimensional structure that may implicate the inactive pro-form of the enzyme in the pathogenesis of the disease