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.
Ng
K K
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MRC of Canada, Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Petersen
J F
JF
Cherney
M M
MM
Garen
C
C
Zalatoris
J J
JJ
Rao-Naik
C
C
Dunn
B M
BM
Martzen
M R
MR
Peanasky
R J
RJ
James
M N
MN
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