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
Source PublicationJOURNAL OF BIOLOGICAL CHEMISTRY
ISSN0021-9258
Volume284Issue:16Pages:10672-10683
AbstractCyclotides 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.
KeywordLigusticum Chuanxiong 4-pentylcyclohex-3-ene-1 Alpha Phthalide Derivatives 2 Beta-diol Ligusticoside a Wallichii Phthalides Constituents Derivatives Rhizomes Dimers
Subject AreaBiochemistry & Molecular Biology
DOI10.1074/jbc.M900021200
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000265104600041
Citation statistics
Cited Times:65[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.kib.ac.cn/handle/151853/4822
Collection植物化学与西部植物资源持续利用国家重点实验室
Affiliation1.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
Recommended Citation
GB/T 7714
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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