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

Nat Struct Biol. 2000 Aug;7(8):653-7. doi: 10.1038/77950.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • Proteins / chemistry*
  • Proteins / metabolism*
  • Sequence Alignment
  • Structure-Activity Relationship
  • Substrate Specificity
  • Swine*

Substances

  • Disulfides
  • Helminth Proteins
  • Pepstatins
  • Protease Inhibitors
  • Proteins
  • pepsin inhibitor PI-3
  • Pepsin A

Associated data

  • PDB/1F32
  • PDB/1F34