The Crystal Structure of PR3, a Neutrophil Serine Proteinase Antigen of Wegener's Granulomatosis Antibodies

Fujinaga, M.; Chernaia, Maia M.; Halenbeck, Robert; Koths, Kirston; James, Michael N.G.

doi:10.1006/jmbi.1996.0458

Cited by 147 publications

(200 citation statements)

References 43 publications

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“…Both loops shape the size and physical character of adjacent subsites around the cleaved peptide bond, namely S1, S1Ј, and S2Ј. The autolysis loop (Gly 145 -Ala 152 ) shows the highest temperature factor of the main chain and is completely disordered in all four PR3 molecules of the asymmetric unit (21). A second region with a high temperature factor maps to the 187-190 loop (21).…”

Section: Discussionmentioning

confidence: 99%

“…The autolysis loop (Gly 145 -Ala 152 ) shows the highest temperature factor of the main chain and is completely disordered in all four PR3 molecules of the asymmetric unit (21). A second region with a high temperature factor maps to the 187-190 loop (21). Such regions are in general preferred target sites for antibody interactions and are good targets for allosteric regulation of enzyme activities.…”

Section: Discussionmentioning

confidence: 99%

“…Although the crystal structure of mature PR3 (without inhibitors bound to it) has been reported (21), inferences about the pro-PR3 structure can be drawn from comparisons with other closely related zymogen-enzyme pairs for which the structures are known. The best studied zymogen-enzyme pair, bovine cationic trypsinogen and its mature counterpart, bovine cationic trypsin (22) (22).…”

Section: Proteinase 3 (Pr3) Is An Abundant Serine Protease Of Neutropmentioning

confidence: 99%

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A Monoclonal Antibody (MCPR3-7) Interfering with the Activity of Proteinase 3 by an Allosteric Mechanism

Hinkofer

Seidel

Korkmaz

et al. 2013

Journal of Biological Chemistry

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Background: Proteinase 3 is an abundant serine protease with high similarity to neutrophil elastase and a major autoimmune target in systemic vasculitis. Results:We identified a monoclonal antibody that inhibits PR3 activity. Conclusion: PR3-inhibiting antibodies can change its conformation and impair interactions with ␣ 1 -proteinase inhibitor. Significance: PR3-inhibiting antibodies may play a role in autoimmune vasculitis and could be exploited as highly selective inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Proteinase 3 (Pr3) Is An Abundant Serine Protease Of Neutropmentioning

confidence: 99%

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A Monoclonal Antibody (MCPR3-7) Interfering with the Activity of Proteinase 3 by an Allosteric Mechanism

Hinkofer

Seidel

Korkmaz

et al. 2013

Journal of Biological Chemistry

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“…The efficacy of catalysis is due in part to a precise binding of substrate with resultant proper orientation of the scissile bond with respect to O␥ of the catalytic serine (17). Fuginaga et al (9) have shown that Pr3 and NE have similar substrate-binding sites that account for their preference for small aliphatic residues at P 1 (4). However, the use of some model substrates and inhibitors indicated that Pr3 is a much poorer catalyst than NE (4, 10 -12).…”

Section: Discussionmentioning

confidence: 99%

“…Fuginaga et al (9) have shown that the two enzymes have similar substrate binding sites. This explains why both proteinases cleave the oxidized insulin A and B chains at peptide bonds involving small aliphatic amino acid residues (4).…”

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Compared Action of Neutrophil Proteinase 3 and Elastase on Model Substrates

Koehl

Knight

Bieth

2003

Journal of Biological Chemistry

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Neutrophil proteinase 3 (Pr3) and elastase (NE) may cause lung tissue destruction in emphysema and cystic fibrosis. These serine proteinases have similar P 1 specificities. We have compared their catalytic activity using acyl-tetrapeptide-p-nitroanilides, which occupy the S 5 -S 1 subsites of their substrate binding site, and intramolecularly quenched fluorogenic heptapeptides, which bind at S 5 -S 4 . Most p-nitroanilide substrates are turned over slowly by Pr3 as compared with NE. These differences disappear with the fluorogenic heptapeptides, some of which are hydrolyzed even faster by Pr3 than by NE. Elongation of substrates strongly increases the catalytic efficiency of Pr3, whereas it has little effect on NE catalysis. These different sensitivities to S-P interactions show that Pr3 and NE are not interchangeable enzymes despite their similar P 1 specificity.The azurophilic granules of polymorphonuclear neutrophils contain three serine proteinases: elastase (NE), 1 cathepsin G, and proteinase 3 (Pr3), which participate in lysosomal bacterial digestion and neutrophil migration through the extracellular matrix at sites of inflammation. These enzymes are ϳ30-kDa glycoproteins, which belong to the chymotrypsin family of serine proteinases. Pr3 is the most recently discovered, the most difficult to isolate, and hence the less well studied proteinase of the three. It is identical to three independently discovered proteins: (i) myeloblastin, which regulates the growth and differentiation of leukemic cells; (ii) p29b, which has microbicidal activity; and (iii) the target antigen of antineutrophil cytoplasmic autoantibodies detected in patients with Wegner's granulomatosis (2). Pr3 cleaves extracellular matrix proteins including elastin, type IV collagen, fibronectin, laminin, and vitronectin (3, 4). It is able to produce lung emphysema in hamsters (3), and thus, in concert with NE and cathepsin G, it may be responsible for lung tissue destruction occurring in emphysema and cystic fibrosis.Although many model substrates have been used to map the active site of NE (5-8), literature on the substrate specificity and the catalytic activity of Pr3 is poorly documented. Fuginaga et al. (9) have shown that the two enzymes have similar substrate binding sites. This explains why both proteinases cleave the oxidized insulin A and B chains at peptide bonds involving small aliphatic amino acid residues (4). The specificity of Pr3 for non-bulky residues has been confirmed with a limited number of model substrates (4, 10 -12). As a rule, these substrates were turned over at a much lower rate by Pr3 than by NE, an unexplained observation. We have undertaken the present work to understand this puzzling finding. EXPERIMENTAL PROCEDURESMaterials-NE was isolated, and active site was titrated as described previously (13). Pr3 came from Athens Research Technology (Athens, GA) and was titrated with ␣ 1 -proteinase inhibitor (4). This enzyme preparation was electrophoretically pure. The presence of NE was tested by reacting 0.14 M Pr3 wi...

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Myeloblastin

Baici¹

2002

Wiley Encyclopedia of Molecular Medicine

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The Crystal Structure of PR3, a Neutrophil Serine Proteinase Antigen of Wegener's Granulomatosis Antibodies

Cited by 147 publications

References 43 publications

A Monoclonal Antibody (MCPR3-7) Interfering with the Activity of Proteinase 3 by an Allosteric Mechanism

A Monoclonal Antibody (MCPR3-7) Interfering with the Activity of Proteinase 3 by an Allosteric Mechanism

Compared Action of Neutrophil Proteinase 3 and Elastase on Model Substrates

Myeloblastin

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