A benzoic acid inhibitor induces a novel conformational change in the active site of Influenza B virus neurarninidase

被引:6
作者
Lommer, BS
Ali, SM
Bajpai, SN
Brouillette, WJ
Air, GM
Luo, M [1 ]
机构
[1] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Dept Chem, Birmingham, AL 35294 USA
[3] Univ Oklahoma, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA
[4] Univ Alabama Birmingham, Ctr Biophys Sci & Engn, Birmingham, AL 35294 USA
来源
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY | 2004年 / 60卷
关键词
D O I
10.1107/S0907444904006225
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Owing to the highly conserved nature of its active site, Influenza B virus neuraminidase (NA) has emerged as a major target for the design of novel anti-influenza drugs. A benzene-ring scaffold has been used in place of the pyranose ring of sialic acid to develop simpler NA inhibitors that contain a minimal number of chiral centers. A new compound belonging to this series, BANA 207, showed significant improvement in inhibitory activity against Influenza B virus NA compared with its parent compound. Here, the structural analysis of a complex of BANA 207 with influenza virus B/Lee/40 NA is reported. The results indicate that BANA 207 forms an unexpected interaction with the crucial active-site residue Glu275 that stabilizes the side chain of this residue in a conformation previously unobserved in NA - inhibitor complexes. This change in the side-chain orientation of Glu275 alters the topology of the triglycerol pocket, which accommodates an additional lipophilic substitution at the benzene ring and may provide an explanation for the increased activity of BANA 207 against Influenza B virus NA.
引用
收藏
页码:1017 / 1023
页数:7
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