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 1.7A 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.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Yu-Shan
authors.initials: YS
authors.lastname: Hsiao
authors.forename: Dane
authors.initials: D
authors.lastname: Parker
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Ratner
authors.forename: Alice
authors.initials: A
authors.lastname: Prince
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D009439:Neuraminidase / Q000737:chemistry*; D011008:Pneumococcal Infections / Q000188:drug therapy; D011487:Protein Conformation; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000900:Anti-Bacterial Agents; D009439:Neuraminidase