Inhibition of the Pneumococcal Virulence Factor StrH and Molecular Insights into N-Glycan Recognition and Hydrolysis

被引：38

作者：

Pluvinage, Benjamin ^{[1
]}

Higgins, Melanie A. ^{[1
]}

Abbott, D. Wade ^{[1
]}

Robb, Craig ^{[1
]}

Dalia, Ankur B. ^{[2
]}

Deng, Lehua ^{[3
]}

Weiser, Jeffrey N. ^{[2
]}

Parsons, Thomas B. ^{[4
]}

Fairbanks, Antony J. ^{[5
]}

Vocadlo, David J. ^{[3
]}

Boraston, Alisdair B. ^{[1
]}

机构：

[1] Univ Victoria, Victoria, BC V8W 3P6, Canada

[2] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA

[3] Simon Fraser Univ, Dept Chem, Burnaby, BC V5A 1S6, Canada

[4] Univ Oxford, Chem Res Lab, Dept Chem, Oxford OX1 3TA, England

[5] Univ Canterbury, Dept Chem, Christchurch 8140, New Zealand

来源：

STRUCTURE | 2011年 / 19卷 / 11期

基金：

加拿大健康研究院; 加拿大自然科学与工程研究理事会;

关键词：

STREPTOCOCCUS-PNEUMONIAE; BETA-HEXOSAMINIDASE; BIOFILM FORMATION; GENOME SEQUENCE; NAG-THIAZOLINE; IN-VITRO; EXOGLYCOSIDASES; COLONIZATION; COMPLEX; MODEL;

D O I：

10.1016/j.str.2011.08.011

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：

The complete degradation of N-linked glycans by the pathogenic bacterium Streptococcus pneumoniae is facilitated by the large multimodular cell wall-attached exo-beta-D-N-acetylglucosaminidase StrH. Structural dissection of this virulence factor using X-ray crystallography showed it to have two structurally related glycoside hydrolase family 20 catalytic domains, which displayed the expected specificity for complex N-glycans terminating in N-acetylglucosamine but exhibited unexpected differences in their preferences for the substructures present in these glycans. The structures of the two catalytic domains in complex with unhydrolyzed substrates, including an N-glycan possessing a bisecting N-acetylglucosamine residue, revealed the specific architectural features in the active sites that confer their differential specificities. Inhibitors of StrH are demonstrated to be effective tools in modulating the interaction of StrH with components of the host, such as the innate immune system. Overall, new structural and functional insight into a carbohydrate-mediated component of the pneumococcus-host interaction is provided.

引用

页码：1603 / 1614

页数：12

共 53 条

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