Structural basis for the inhibition of porcine pepsin by Ascaris pepsin inhibitor-3.
The three-dimensional structures of pepsin inhibitor-3 (PI-3) from Ascaris suum and of the complex between PI-3 and porcine pepsin at 1. 75 A and 2.45 A resolution, respectively, have revealed the mechanism of aspartic protease inhibition by this unique inhibitor. PI-3 has a new fold consisting of two domains, each comprising an antiparallel beta-sheet flanked by an alpha-helix. In the enzyme-inhibitor complex, the N-terminal beta-strand of PI-3 pairs with one strand of the 'active site flap' (residues 70-82) of pepsin, thus forming an eight-stranded beta-sheet that spans the two proteins. PI-3 has a novel mode of inhibition, using its N-terminal residues to occupy and therefore block the first three binding pockets in pepsin for substrate residues C-terminal to the scissile bond (S1'-S3'). The molecular structure of the pepsin-PI-3 complex suggests new avenues for the rational design of proteinaceous aspartic proteinase inhibitors.
MRC of Canada, Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
K K
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Ng
J F
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Petersen
M M
MM
Cherney
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Garen
J J
JJ
Zalatoris
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Rao-Naik
B M
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Dunn
M R
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Martzen
R J
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Peanasky
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James
D000595:Amino Acid Sequence; D000818:Animals; D017165:Ascaris suum / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000378:metabolism; D015801:Helminth Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010434:Pepsin A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010436:Pepstatins / Q000737:chemistry* / Q000378:metabolism*; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
D004220:Disulfides; D015801:Helminth Proteins; D010436:Pepstatins; D011480:Protease Inhibitors; D011506:Proteins; C410352:pepsin inhibitor PI-3; D010434:Pepsin A