PDBsum entry 4zj4

Hydrolase-hydrolase inhibitor

PDB id: 4zj4

Contents

Protein chain

239 a.a.

Ligands

CYS-PRO-ALA-ARG-PHE-ALA-ALA-LEU-PHE-CYS

SO4 ×5

MRZ

Waters ×201

References listed in PDB file

Key reference

• Title: Design of specific serine protease inhibitors based on a versatile peptide scaffold: conversion of a urokinase inhibitor to a plasma kallikrein inhibitor.
• Authors: P.Xu, M.Xu, L.Jiang, Q.Yang, Z.Luo, Z.Dauter, M.Huang, P.A.Andreasen.
• Ref.: J Med Chem, 2015, 58, 8868-8876. [DOI no: 10.1021/acs.jmedchem.5b01128]
• PubMed id: 26536069

Abstract

All serine proteases hydrolyze peptide bonds by the same basic mechanism and have very similar active sites, in spite of the fact that individual proteases have different physiological functions. We here report a strategy for designing high-affinity and high-specificity serine protease inhibitors using a versatile peptide scaffold, a 10-mer peptide, mupain-1 (CPAYSRYLDC). Mupain-1 was previously reported as a specific inhibitor of murine urokinase-type plasminogen activator (Ki = 0.55 μM) without measurable affinity to plasma kallikrein (Ki > 1000 μM). On the basis of a structure-based rational design, we substituted five residues of mupain-1 and converted it to a potent plasma kallikrein inhibitor (Ki = 0.014 μM). X-ray crystal structure analysis showed that the new peptide was able to adapt a new set of enzyme surface interactions by a slightly changed backbone conformation. Thus, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases.