4YW5

Crystal Structure of Streptococcus pneumoniae NanC, complex with oseltamivir carboxylate

Summary for 4YW5

• Entry DOI: 10.2210/pdb4yw5/pdb
• Descriptor: Neuraminidase C, (3R,4R,5S)-4-(acetylamino)-5-amino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid, GLYCEROL, ... (5 entities in total)
• Functional Keywords: sialidase, neuraminidase, oseltamivir, cbm40, hydrolase
• Biological source: Streptococcus pneumoniae serotype 4 (strain ATCC BAA-334 / TIGR4)
• Total number of polymer chains: 2
• Total formula weight: 149416.83

Authors

Owen, C.D.,Lukacik, P.,Potter, J.A.,Walsh, M.,Taylor, G.L. (deposition date: 2015-03-20, release date: 2015-09-23, Last modification date: 2024-01-10)

Primary citation

Owen, C.D.,Lukacik, P.,Potter, J.A.,Sleator, O.,Taylor, G.L.,Walsh, M.A.
Streptococcus pneumoniae NanC: STRUCTURAL INSIGHTS INTO THE SPECIFICITY AND MECHANISM OF A SIALIDASE THAT PRODUCES A SIALIDASE INHIBITOR.
J.Biol.Chem., 290:27736-27748, 2015

PubMed Abstract: Streptococcus pneumoniae is an important human pathogen that causes a range of disease states. Sialidases are important bacterial virulence factors. There are three pneumococcal sialidases: NanA, NanB, and NanC. NanC is an unusual sialidase in that its primary reaction product is 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en, also known as DANA), a nonspecific hydrolytic sialidase inhibitor. The production of Neu5Ac2en from α2-3-linked sialosides by the catalytic domain is confirmed within a crystal structure. A covalent complex with 3-fluoro-β-N-acetylneuraminic acid is also presented, suggesting a common mechanism with other sialidases up to the final step of product formation. A conformation change in an active site hydrophobic loop on ligand binding constricts the entrance to the active site. In addition, the distance between the catalytic acid/base (Asp-315) and the ligand anomeric carbon is unusually short. These features facilitate a novel sialidase reaction in which the final step of product formation is direct abstraction of the C3 proton by the active site aspartic acid, forming Neu5Ac2en. NanC also possesses a carbohydrate-binding module, which is shown to bind α2-3- and α2-6-linked sialosides, as well as N-acetylneuraminic acid, which is captured in the crystal structure following hydration of Neu5Ac2en by NanC. Overall, the pneumococcal sialidases show remarkable mechanistic diversity while maintaining a common structural scaffold.

PubMed: 26370075
DOI: 10.1074/jbc.M115.673632

Experimental method

X-RAY DIFFRACTION (2.3 Å)