Structural basis for the inhibition of porcine pepsin by Ascaris pepsin inhibitor-3

• Published in: Nature structural & molecular biology Vol. 7; no. 8; pp. 653 - 657
• Main Authors: James, Michael N.G, Ng, Kenneth K.S, Petersen, Jens F.W, Cherney, Maia M, Garen, Craig, Zalatoris, Jeffrey J, Rao-Naik, Chetana, Dunn, Ben M, Martzen, Mark R, Peanasky, Robert J
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.08.2000
• Subjects: Amino Acid Sequence; Animals; Ascaris suum - chemistry; Binding Sites; Crystallography, X-Ray; Disulfides - metabolism; Helminth Proteins; Models, Molecular; Molecular Sequence Data; Pepsin A - antagonists & inhibitors; Pepsin A - metabolism; Pepstatins - chemistry; Pepstatins - metabolism; Protease Inhibitors - chemistry; Protease Inhibitors - metabolism; Protein Binding; Protein Structure, Secondary; Proteinase inhibitors; Proteins - chemistry; Proteins - metabolism; Sequence Alignment; Structure-Activity Relationship; Substrate Specificity; Swine
• ISSN: 1072-8368; 1545-9993; 2331-365X; 1545-9985
• DOI: 10.1038/77950

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 Å and 2.45 Å 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 β-sheet flanked by an α-helix. In the enzyme-inhibitor complex, the N-terminal β-strand of PI-3 pairs with one strand of the 'active site flap' (residues 70-82) of pepsin, thus forming an eight-stranded β-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.