Circular Proteins in Plants

Felizmenio-Quimio, M.E.; Daly, Norelle L.; Craik, David J.

doi:10.1074/jbc.m101666200

Cited by 212 publications

(160 citation statements)

References 40 publications

(56 reference statements)

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“…MCoTI-II synthesised by this chemoenzymatic method was identical in all respects to naturally occurring MCoTI-II. 18,19,29,36 Interestingly, concomitant release of a small amount (8%) of rf-MCoTI-II is observed, although it was absent from the This facile new route to MCoTI-II was explored in a series of experiments that show that PST possesses ligase specificity for positively charged (Arg/Lys) residues at P 1 in the inhibitory loop. The open-chain forms of the naturally 50 occurring cyclotide MCoTI-I (P 1 =Lys) and three MCoTI-II analogues in which P 1 was changed to Arg, Gln or Phe (Table 2) were synthesised by SPPS, and subjected to the refolding and PST-mediated ligation conditions described above.…”

Section: Chemoenzymatic Synthesis Of Engineered Mcoti Cyclotidesmentioning

confidence: 99%

“…23 Syntheses of several small to 35 medium size cyclotides have been reported [24][25][26][27][28] The cyclotides MCoTI-I and MCoTI-II were first isolated from the dormant seeds of Momordica cochinchinensis, and have been shown to be very potent (sub-nM) inhibitors of trypsin. 18 Whilst the MCoTI trypsin inhibitor cyclotides do 40 not share significant sequence homology with other cyclotides beyond the presence of the three cystine bridges, solution NMR has shown that they do indeed adopt a backbone-cyclic cystine-knot topology (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…18,36 Key residues in the active loop (Pro9, Lys10, Ile11) and the cystine bridges are highlighted. Red: alpha helix; green: backbone; yellow: disulfide bridges.…”

Section: Introductionmentioning

confidence: 99%

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Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides

et al. 2008

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The naturally-occurring cyclic cystine-knot microprotein trypsin inhibitors MCoTI-I and MCoTI-II have been synthesised using both thia-zip native chemical ligation and a biomimetic strategy featuring chemoenzymatic cyclisation by an immobilised protease. Engineered analogues have been produced containing a range of substitutions at the P 1 position that redirect specificity 10 towards alternative protease targets whilst retaining excellent to moderate affinity. Furthermore, we report an MCoTI analogue that is a selective low-µM inhibitor of foot-and-mouth-disease virus (FMDV) 3C protease, the first reported inhibitor of this important viral enzyme.

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Section: Chemoenzymatic Synthesis Of Engineered Mcoti Cyclotidesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides

et al. 2008

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“…[4] The third subfamily, the trypsin inhibitor cyclotides, comprises only two members, which are present in the seeds of Momordica cochinchinensis, a tropical vine from the Cucurbitaceae plant family. Although the trypsin inhibitor cyclotides have the CCK motif, their amino acid sequences differ significantly from those of Möbius and bracelet cyclotides [15,27] but are similar to a family of linear squash trypsin inhibitors. [28] They are also referred to as cyclic knottins.…”

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confidence: 99%

“…Three-dimensional structures and sequences of selected cyclotides from each of the three subfamilies. The structures of kalata B1 (PDB ID code 1nb1), [36] cycloviolacin O1 (PDB ID code 1nbj), [36] and MCoTI-II (PDB ID code 1ib9) [27] are shown with the lowest-energy structure on top and an ensemble of the 20 lowest-energy structures below. The structures were drawn using MOLMOL.…”

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Structure and Activity of the Leaf-Specific Cyclotide vhl-2

et al. 2010

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Cyclotides are plant-derived macrocyclic peptides with potential applications in the pharmaceutical and agricultural industries. In addition to their presumed natural function as host-defence peptides arising from their insecticidal activity, their other biological activities include antimicrobial, haemolytic, and cytotoxic activities, but at present, only limited information is available on the structural and chemical features that are important for these various activities. In the current study, we determined the three-dimensional structure of vhl-2, a leaf-specific cyclotide. Although the characteristic cyclic cystine knot fold of other cyclotides is maintained in vhl-2, it has more potent haemolytic activity than well-characterized cyclotides such as kalata B1 and kalata B8. Analysis of surface hydrophobicity and haemolytic activity for a range of cyclotides indicates a correlation between them, with increasing hydrophobicity resulting in increased haemolytic activity. This correlation is consistent with membrane binding being a vital step in mediating the various cytotoxic activities of cyclotides. The gene sequence for vhl-2 was determined and indicates that vhl-2 is processed from a multidomain precursor protein that also encodes the cyclotide cycloviolacin H3.

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Cyclotides

Dörnenburg

Craik

2010

Encyclopedia of Industrial Biotechnology

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The cyclotides are a recently discovered family of miniproteins that contain a head‐to‐tail cyclized backbone and a knotted arrangement of disulfide bonds. They are approximately 30 amino acids in size and are present in high abundance in plants from the Rubiaceae, Violaceae, and Cucurbitaceae families, with individual plants containing a suite of up to 100 cyclotides. They have a diverse range of bioactivities, including uterotonic, anti‐HIV, antitumor, and antimicrobial activities, although their natural function is believed to be in host defence against pests and pathogens. In addition to their natural activities, cyclotides have been proposed as a stable peptide template for applications in protein engineering and drug design. Their exceptional stability and resistance to thermal, chemical or enzymatic treatments can be attributed to the cyclic cystine knot structural motif that forms their compact molecular core. The backbone loops protruding from this core vary in their amino acid compositions and because of this tolerance to substitutions, cyclotides can be regarded as a natural combinatorial template. To date, most bioactivity studies on cyclotides have involved peptides extracted from plants. Cyclotides are amenable to chemical synthesis but this is expensive and so the development of bioprocesses for the production of cyclotides is an important objective for enabling their future industrial applications. This article gives a brief overview of the structures and properties of cyclotides and discusses new approaches to their production using bioprocesses on an industrial scale.

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Circular Proteins in Plants

Abstract: Much interest has been generated by recent reports on the discovery of circular (i.e. head-to-tail cyclized) proteins in plants. Here

Cited by 212 publications

References 40 publications

Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides

Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides

Structure and Activity of the Leaf-Specific Cyclotide vhl-2

Cyclotides

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