Crystal structure of the catalytic domain of Clostridium perfringens neuraminidase in complex with a non-carbohydrate-based inhibitor, 2-(cyclohexylamino)ethanesulfonic acid.
Anti-bacterial and anti-viral neuraminidase agents inhibit neuraminidase activity catalyzing the hydrolysis of terminal N-acetylneuraminic acid (Neu5Ac) from glycoconjugates and help to prevent the host pathogenesis that lead to fatal infectious diseases including influenza, bacteremia, sepsis, and cholera. Emerging antibiotic and drug resistances to commonly used anti-neuraminidase agents such as oseltamivir (Tamiflu) and zanamivir (Relenza) have highlighted the need to develop new anti-neuraminidase drugs. We obtained a serendipitous complex crystal of the catalytic domain of Clostridium perfringens neuraminidase (CpNanICD) with 2-(cyclohexylamino)ethanesulfonic acid (CHES) as a buffer. Here, we report the crystal structure of CpNanICDin complex with CHES at 1.24 Å resolution. Amphipathic CHES binds to the catalytic site of CpNanICDsimilar to the substrate (Neu5Ac) binding site. The 2-aminoethanesulfonic acid moiety and cyclohexyl groups of CHES interact with the cluster of three arginine residues and with the hydrophobic pocket of the CpNanICDcatalytic site. In addition, a structural comparison with other bacterial and human neuraminidases suggests that CHES could serve as a scaffold for the development of new anti-neuraminidase agents targeting CpNanI.
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea; Steitz Center for Structural Biology, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
Youngjin
Y
Lee
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea; Steitz Center for Structural Biology, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
Hyung-Seop
HS
Youn
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea; Steitz Center for Structural Biology, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
Jung-Gyu
JG
Lee
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea; Steitz Center for Structural Biology, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
Jun Yop
JY
An
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea; Steitz Center for Structural Biology, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
Kyoung Ryoung
KR
Park
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea; Steitz Center for Structural Biology, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
Jung Youn
JY
Kang
Natural Product Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 56212, Republic of Korea.
Young Bae
YB
Ryu
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
Mi Sun
MS
Jin
Division of Applied Life Science (BK21 plus), IALS, Gyeongsang National University, Jinju 52828, Republic of Korea.
Ki Hun
KH
Park
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea; Steitz Center for Structural Biology, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea; Department of Chemistry, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea. Electronic address: eom@gist.ac.kr.
Soo Hyun
SH
Eom
D020816:Amino Acid Motifs; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D003001:Cloning, Molecular; D003016:Clostridium perfringens / Q000737:chemistry* / Q000201:enzymology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D008958:Models, Molecular; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein; D013654:Taurine / Q000031:analogs & derivatives* / Q000737:chemistry
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C050927:2-(N-cyclohexylamino)ethanesulfonic acid; D013654:Taurine; D009439:Neuraminidase
Anti-neuraminidase agents; CHES; Clostridium perfringens; Crystal structure; NanI; Neuraminidase