RESUMEN

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.

Asunto(s)

Ascaris suum/química , Pepsina A/antagonistas & inhibidores , Pepsina A/metabolismo , Pepstatinas/química , Pepstatinas/metabolismo , Proteínas/química , Proteínas/metabolismo , Porcinos , Secuencia de Aminoácidos , Animales , Sitios de Unión , Cristalografía por Rayos X , Disulfuros/metabolismo , Proteínas del Helminto , Modelos Moleculares , Datos de Secuencia Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Unión Proteica , Estructura Secundaria de Proteína , Alineación de Secuencia , Relación Estructura-Actividad , Especificidad por Sustrato