Resisting degradation by human elastase: Commonality of design features shared by 'canonical' plant and bacterial macrocyclic protease inhibitor scaffolds

被引：4

作者：

Brauer, Arnd B. E.

McBride, Jeffrey D.

Kelly, Geoff

Matthews, Stephen J.

Leatherbarrow, Robin J.

机构：

[1] Imperial Coll London, Dept Chem, London SW7 2AZ, England

[2] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany

[3] UCL Hosp, Dept Virol, London W1T 4JF, England

[4] Natl Inst Med Res, MRC, Biomed NMR Ctr, London NW7 1AA, England

[5] Imperial Coll London, Dept Biol Sci, London SW7 2AZ, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2007年 / 15卷 / 13期

基金：

英国医学研究理事会;

关键词：

P2; threonine; human elastase; Bowman-Birk serine protease inhibitor; depsipeptides;

D O I：

10.1016/j.bmc.2007.03.082

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A previously unexplained difference in the resistance to enzymatic hydrolysis of 11-mer Bowman-Birk-type inhibitors of human leukocyte elastase that differ in PI is found to correlate with the strength of a particular intramolecular hydrogen bond within the inhibitor. This transarmular hydrogen bond stabilizes the side chain of the conserved P2 Thr in a 'canonical' +60 degrees-rotamer X, conformation and thereby directs it for a close interaction with the enzyme's catalytic His. As the implications of this NMR analysis are neither limited to this macrocyclic scaffold derived from plant proteins nor to a particular scrine protease, we present a unified analysis with inhibitory bacterial depsipeptides of 7-12 residues in length that share key design features for which we propose communal functional explanations. (c) 2007 Elsevier Ltd. All rights reserved.

引用

页码：4618 / 4628

页数：11

共 97 条

[41]

Hudáky P, 2006, PROTEINS, V62, P749, DOI 10.1002/prot.20872

[42] Solution structure of a novel C2-symmetrical bifunctional bicyclic inhibitor based on SFTI-1 [J].