Crystal Structures of Respiratory Pathogen Neuraminidases

Overview

Journal Biochem Biophys Res Commun

Publisher Elsevier

Specialty Biochemistry

Date 2009 Mar 17

PMID 19284989

Citations 18

Authors

Yu-Shan Hsiao

Dane Parker

Adam J Ratner

Alice Prince

Liang Tong

Affiliations

Soon will be listed here.

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.

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References

Xu G, Li X, Andrew P, Taylor G . Structure of the catalytic domain of Streptococcus pneumoniae sialidase NanA. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008; 64(Pt 9):772-5. PMC: 2531273. DOI: 10.1107/S1744309108024044. View

Crennell S, Garman E, Philippon C, Vasella A, Laver W, Vimr E . The structures of Salmonella typhimurium LT2 neuraminidase and its complexes with three inhibitors at high resolution. J Mol Biol. 1996; 259(2):264-80. DOI: 10.1006/jmbi.1996.0318. View

Brunger A, Adams P, Clore G, DeLano W, Gros P, Grosse-Kunstleve R . Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr. 1998; 54(Pt 5):905-21. DOI: 10.1107/s0907444998003254. View

Otwinowski Z, Minor W . Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997; 276:307-26. DOI: 10.1016/S0076-6879(97)76066-X. View

Roggentin P, Schauer R, Hoyer L, Vimr E . The sialidase superfamily and its spread by horizontal gene transfer. Mol Microbiol. 1993; 9(5):915-21. DOI: 10.1111/j.1365-2958.1993.tb01221.x. View

Lanotte P, Watt S, Mereghetti L, Dartiguelongue N, Rastegar-Lari A, Goudeau A . Genetic features of Pseudomonas aeruginosa isolates from cystic fibrosis patients compared with those of isolates from other origins. J Med Microbiol. 2003; 53(Pt 1):73-81. DOI: 10.1099/jmm.0.05324-0. View

King S, Hippe K, Weiser J . Deglycosylation of human glycoconjugates by the sequential activities of exoglycosidases expressed by Streptococcus pneumoniae. Mol Microbiol. 2006; 59(3):961-74. DOI: 10.1111/j.1365-2958.2005.04984.x. View

Amaya M, Buschiazzo A, Nguyen T, Alzari P . The high resolution structures of free and inhibitor-bound Trypanosoma rangeli sialidase and its comparison with T. cruzi trans-sialidase. J Mol Biol. 2003; 325(4):773-84. DOI: 10.1016/s0022-2836(02)01306-2. View

Carr J, Ives J, Kelly L, Lambkin R, Oxford J, MENDEL D . Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo. Antiviral Res. 2002; 54(2):79-88. DOI: 10.1016/s0166-3542(01)00215-7. View

10.

Sadikot R, Blackwell T, Christman J, Prince A . Pathogen-host interactions in Pseudomonas aeruginosa pneumonia. Am J Respir Crit Care Med. 2005; 171(11):1209-23. PMC: 2718459. DOI: 10.1164/rccm.200408-1044SO. View

11.

Brueggemann A, Pai R, Crook D, Beall B . Vaccine escape recombinants emerge after pneumococcal vaccination in the United States. PLoS Pathog. 2007; 3(11):e168. PMC: 2077903. DOI: 10.1371/journal.ppat.0030168. View

12.

Crennell S, Garman E, Laver G, Vimr E, Taylor G . Crystal structure of Vibrio cholerae neuraminidase reveals dual lectin-like domains in addition to the catalytic domain. Structure. 1994; 2(6):535-44. DOI: 10.1016/s0969-2126(00)00053-8. View

13.

Gut H, King S, Walsh M . Structural and functional studies of Streptococcus pneumoniae neuraminidase B: An intramolecular trans-sialidase. FEBS Lett. 2008; 582(23-24):3348-52. DOI: 10.1016/j.febslet.2008.08.026. View

14.

Krissinel E, Henrick K . Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 12 Pt 1):2256-68. DOI: 10.1107/S0907444904026460. View

15.

Nicholls A, Sharp K, Honig B . Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins. 1991; 11(4):281-96. DOI: 10.1002/prot.340110407. View

16.

King S, Hippe K, Gould J, Bae D, Peterson S, Cline R . Phase variable desialylation of host proteins that bind to Streptococcus pneumoniae in vivo and protect the airway. Mol Microbiol. 2004; 54(1):159-71. DOI: 10.1111/j.1365-2958.2004.04252.x. View

17.

Fong S, Hamill S, Proctor M, Freund S, Benian G, Chothia C . Structure and stability of an immunoglobulin superfamily domain from twitchin, a muscle protein of the nematode Caenorhabditis elegans. J Mol Biol. 1996; 264(3):624-39. DOI: 10.1006/jmbi.1996.0665. View

18.

Orihuela C, Gao G, Francis K, Yu J, Tuomanen E . Tissue-specific contributions of pneumococcal virulence factors to pathogenesis. J Infect Dis. 2004; 190(9):1661-9. DOI: 10.1086/424596. View

19.

Gaskell A, Crennell S, Taylor G . The three domains of a bacterial sialidase: a beta-propeller, an immunoglobulin module and a galactose-binding jelly-roll. Structure. 1995; 3(11):1197-205. DOI: 10.1016/s0969-2126(01)00255-6. View

20.

King S, Whatmore A, Dowson C . NanA, a neuraminidase from Streptococcus pneumoniae, shows high levels of sequence diversity, at least in part through recombination with Streptococcus oralis. J Bacteriol. 2005; 187(15):5376-86. PMC: 1196044. DOI: 10.1128/JB.187.15.5376-5386.2005. View