Combined X-ray and NMR Analysis of the Stability of the Cyclotide Cystine Knot Fold That Underpins Its Insecticidal Activity and Potential Use as a Drug Scaffold
Wang, Conan K.1; Hu, Shu-Hong1; Martin, Jennifer L.1; Sjogren, Tove2; Hajdu, Janos2; Bohlin, Lars3; Claeson, Per3; Goransson, Ulf3; Rosengren, K. Johan1,3; Tang, Jun4; Tan, Ning-Hua4; Craik, David J.1
2009-04-17
发表期刊JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN0021-9258
卷号284期号:16页码:10672-10683
摘要Cyclotides are a family of plant defense proteins that are highly resistant to adverse chemical, thermal, and enzymatic treatment. Here, we present the first crystal structure of a cyclotide, varv F, from the European field pansy, Viola arvensis, determined at a resolution of 1.8 angstrom. The solution state NMR structure was also determined and, combined with measurements of biophysical parameters for several cyclotides, provided an insight into the structural features that account for the remarkable stability of the cyclotide family. The x-ray data confirm the cystine knot topology and the circular backbone, and delineate a conserved network of hydrogen bonds that contribute to the stability of the cyclotide fold. The structural role of a highly conserved Glu residue that has been shown to regulate cyclotide function was also determined, verifying its involvement in a stabilizing hydrogen bond network. We also demonstrate that varv F binds to dodecylphosphocholine micelles, defining the binding orientation and showing that its structure remains unchanged upon binding, further demonstrating that the cyclotide fold is rigid. This study provides a biological insight into the mechanism by which cyclotides maintain their native activity in the unfavorable environment of predator insect guts. It also provides a structural basis for explaining how a cluster of residues important for bioactivity may be involved in self-association interactions in membranes. As well as being important for their bioactivity, the structural rigidity of cyclotides makes them very suitable as a stable template for peptide-based drug design.
关键词Ligusticum Chuanxiong 4-pentylcyclohex-3-ene-1 Alpha Phthalide Derivatives 2 Beta-diol Ligusticoside a Wallichii Phthalides Constituents Derivatives Rhizomes Dimers
资助信息Australian Research Council
学科领域Biochemistry & Molecular Biology
DOI10.1074/jbc.M900021200
收录类别SCI
语种英语
WOS研究方向Biochemistry & Molecular Biology
WOS类目Biochemistry & Molecular Biology
WOS记录号WOS:000265104600041
引用统计
被引频次:62[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/4822
专题植物化学与西部植物资源持续利用国家重点实验室
作者单位1.Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia
2.Uppsala Univ, Dept Cellular & Mol Biol, Biomed Ctr, SE-75124 Uppsala, Sweden
3.Uppsala Univ, Dept Med Chem, Biomed Ctr, SE-75123 Uppsala, Sweden
4.Chinese Acad Sci, State Key Lab Phytochem & Plant Resources W China, Kunming Inst Bot, Kunming 650204, Yunnan, Peoples R China
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Wang, Conan K.,Hu, Shu-Hong,Martin, Jennifer L.,et al. Combined X-ray and NMR Analysis of the Stability of the Cyclotide Cystine Knot Fold That Underpins Its Insecticidal Activity and Potential Use as a Drug Scaffold[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2009,284(16):10672-10683.
APA Wang, Conan K..,Hu, Shu-Hong.,Martin, Jennifer L..,Sjogren, Tove.,Hajdu, Janos.,...&Craik, David J..(2009).Combined X-ray and NMR Analysis of the Stability of the Cyclotide Cystine Knot Fold That Underpins Its Insecticidal Activity and Potential Use as a Drug Scaffold.JOURNAL OF BIOLOGICAL CHEMISTRY,284(16),10672-10683.
MLA Wang, Conan K.,et al."Combined X-ray and NMR Analysis of the Stability of the Cyclotide Cystine Knot Fold That Underpins Its Insecticidal Activity and Potential Use as a Drug Scaffold".JOURNAL OF BIOLOGICAL CHEMISTRY 284.16(2009):10672-10683.
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