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Title: Crystal Structures of Respiratory Pathogen Neuraminidases

Abstract

Currently there is pressing need to develop novel therapeutic agents for the treatment of infections by the human respiratory pathogens Pseudomonas aeruginosa and Streptococcus pneumoniae. The neuraminidases of these pathogens are important for host colonization in animal models of infection and are attractive targets for drug discovery. To aid in the development of inhibitors against these neuraminidases, we have determined the crystal structures of the P. aeruginosa enzyme NanPs and S. pneumoniae enzyme NanA at 1.6 and 1.7 {angstrom} resolution, respectively. In situ proteolysis with trypsin was essential for the crystallization of our recombinant NanA. The active site regions of the two enzymes are strikingly different. NanA contains a deep pocket that is similar to that in canonical neuraminidases, while the NanPs active site is much more open. The comparative studies suggest that NanPs may not be a classical neuraminidase, and may have distinct natural substrates and physiological functions. This work represents an important step in the development of drugs to prevent respiratory tract colonization by these two pathogens.

Authors:
; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
980117
Report Number(s):
BNL-93035-2010-JA
Journal ID: ISSN 0006-291X; BBRCA9; TRN: US201015%%1502
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 380; Journal Issue: 3
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; 59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; ANIMALS; CRYSTAL STRUCTURE; CRYSTALLIZATION; DRUGS; ENZYMES; FUNCTIONS; HOST; HUMAN POPULATIONS; PATHOGENS; PROTEOLYSIS; PSEUDOMONAS; RESPIRATORY SYSTEM; STREPTOCOCCUS; SUBSTRATES; TARGETS; TRYPSIN; national synchrotron light source

Citation Formats

Hsiao, Y., Parker, D, Ratner, A, Prince, A, and Tong, L. Crystal Structures of Respiratory Pathogen Neuraminidases. United States: N. p., 2009. Web. doi:10.1016/j.bbrc.2009.01.108.
Hsiao, Y., Parker, D, Ratner, A, Prince, A, & Tong, L. Crystal Structures of Respiratory Pathogen Neuraminidases. United States. doi:10.1016/j.bbrc.2009.01.108.
Hsiao, Y., Parker, D, Ratner, A, Prince, A, and Tong, L. 2009. "Crystal Structures of Respiratory Pathogen Neuraminidases". United States. doi:10.1016/j.bbrc.2009.01.108.
@article{osti_980117,
title = {Crystal Structures of Respiratory Pathogen Neuraminidases},
author = {Hsiao, Y. and Parker, D and Ratner, A and Prince, A and Tong, L},
abstractNote = {Currently there is pressing need to develop novel therapeutic agents for the treatment of infections by the human respiratory pathogens Pseudomonas aeruginosa and Streptococcus pneumoniae. The neuraminidases of these pathogens are important for host colonization in animal models of infection and are attractive targets for drug discovery. To aid in the development of inhibitors against these neuraminidases, we have determined the crystal structures of the P. aeruginosa enzyme NanPs and S. pneumoniae enzyme NanA at 1.6 and 1.7 {angstrom} resolution, respectively. In situ proteolysis with trypsin was essential for the crystallization of our recombinant NanA. The active site regions of the two enzymes are strikingly different. NanA contains a deep pocket that is similar to that in canonical neuraminidases, while the NanPs active site is much more open. The comparative studies suggest that NanPs may not be a classical neuraminidase, and may have distinct natural substrates and physiological functions. This work represents an important step in the development of drugs to prevent respiratory tract colonization by these two pathogens.},
doi = {10.1016/j.bbrc.2009.01.108},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 380,
place = {United States},
year = 2009,
month = 1
}
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