title: Structural basis of sialidase in complex with geranylated flavonoids as potent natural inhibitors.
abstract: Sialidase catalyzes the removal of a terminal sialic acid from glycoconjugates and plays a pivotal role in nutrition, cellular interactions and pathogenesis mediating various infectious diseases including cholera, influenza and sepsis. An array of antiviral sialidase agents have been developed and are commercially available, such as zanamivir and oseltamivir for treating influenza. However, the development of bacterial sialidase inhibitors has been much less successful. Here, natural polyphenolic geranylated flavonoids which show significant inhibitory effects against Cp-NanI, a sialidase from Clostridium perfringens, are reported. This bacterium causes various gastrointestinal diseases. The crystal structure of the Cp-NanI catalytic domain in complex with the best inhibitor, diplacone, is also presented. This structure explains how diplacone generates a stable enzyme-inhibitor complex. These results provide a structural framework for understanding the interaction between sialidase and natural flavonoids, which are promising scaffolds on which to discover new anti-sialidase agents.
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Youngjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Infection Control Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185, Republic of Korea.
authors.forename: Young Bae
authors.initials: YB
authors.lastname: Ryu
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Hyung-Seop
authors.initials: HS
authors.lastname: Youn
authors.affiliation: Division of Applied Life Science (BK21 Program, IALS), Graduate School of Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Jung Keun
authors.initials: JK
authors.lastname: Cho
authors.affiliation: Infection Control Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185, Republic of Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Infection Control Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Infection Control Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185, Republic of Korea.
authors.forename: Woo Song
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Division of Applied Life Science (BK21 Program, IALS), Graduate School of Gyeongsang National University, Jinju 660-701, Republic of Korea.
authors.forename: Ki Hun
authors.initials: KH
authors.lastname: Park
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Buk-gu, Gwangju 500-712, Republic of Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Eom
mesh_terms: D020134:Catalytic Domain; D003016:Clostridium perfringens / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D044950:Flavanones / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D004791:Enzyme Inhibitors; D044950:Flavanones; D005419:Flavonoids; D009439:Neuraminidase
keywords: NanI; diplacone; geranylated flavonoid; sialidase; sialidase inhibitor