KNOTTIN: the database of inhibitor cystine knot scaffold after 10 years, toward a systematic structure modeling

Postic, Guillaume; Gracy, Jérôme; Périn, Charlotte; Chiche, Laurent; Gelly, Jean‐Christophe

doi:10.1093/nar/gkx1084

Cited by 92 publications

(82 citation statements)

References 22 publications

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“…Many spider venoms appeared to have evolved primarily by explosive duplication and neofunctionalization of a single ancestral gene encoding a disulfide‐rich knottin peptide . Knotttins are small peptides (typically 30–50 amino acid residues) that conform to a protein fold known as an inhibitor cystine knot (ICK) motif . The ICK motif comprises a two‐ or three‐stranded β‐sheet stabilized by three disulfide bonds that form a pseudo‐knot in which two of the disulfide bonds and the intervening sections of the polypeptide backbone form a closed loop that is bisected by the third disulfide (Fig.…”

Section: Knotted Spider‐venom Peptides: Potent Stable and Orally Acmentioning

confidence: 99%

Tying pest insects in knots: the deployment of spider‐venom‐derived knottins as bioinsecticides

King

2019

Pest Management Science

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Spider venoms are complex chemical arsenals that contain a rich variety of insecticidal toxins. However, the major toxin class in many spider venoms is disulfide‐rich peptides known as knottins. The knotted three‐dimensional fold of these mini‐proteins provides them with exceptional chemical and thermal stability as well as resistance to proteases. In contrast with other bioinsecticides, which are often slow‐acting, spider knottins are fast‐acting neurotoxins. In addition to being potently insecticidal, some knottins have exceptional taxonomic selectivity, being lethal to key agricultural pests but innocuous to vertebrates and beneficial insects such as bees. The intrinsic oral activity of these peptides, combined with the ability of aerosolized knottins to penetrate insect spiracles, has enabled them to be developed commercially as eco‐friendly bioinsecticides. Moreover, it has been demonstrated that spider‐knottin transgenes can be used to engineer faster‐acting entomopathogens and insect‐resistant crops. © 2019 Society of Chemical Industry

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Section: Knotted Spider‐venom Peptides: Potent Stable and Orally Acmentioning

confidence: 99%

Tying pest insects in knots: the deployment of spider‐venom‐derived knottins as bioinsecticides

King

2019

Pest Management Science

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“…1a ), often conferring extreme thermal, chemical, and proteolytic stability 1 – 4 . Archetypes of such peptides, with cores of at least three cystines, include “ inhibitor cystine knot peptides ”, or knottins, and the closely-related “ cyclic cystine knot peptides ”, or cyclotides 5 , 6 . Examples include venom toxins from cone snails, spiders, and scorpions; plant protease inhibitors; and antimicrobial defensins.…”

Section: Introductionmentioning

confidence: 99%

Screening, large-scale production and structure-based classification of cystine-dense peptides

Correnti¹,

Gewe²,

Mehlin³

et al. 2018

Nat Struct Mol Biol

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Peptides folded through interwoven disulfides display extreme biochemical properties and unique medicinal potential. Their exploitation was hampered by the limited amounts isolatable from natural sources and the expense of chemical synthesis. We developed reliable biological methods for high-throughput expression screening and large-scale production of these peptides. 46 were successfully produced in multimilligram quantities, and over 600 more were deemed expressible by stringent screening criteria. Many showed extreme resistance to temperature, proteolysis, and/or reduction, and all displayed inhibitory activity against at least one of 20 ion channels tested, confirming biological functionality. Crystal structures of 12 were determined, confirming proper cystine topology, and the utility of crystallography for studying these molecules, but highlighted the need for rational classification. Previous attempts at categorization have focused on limited subsets siloed around distinct motifs. Stepping back, we present a global definition, classification, and analysis of over 700 structures of cystine-dense peptides, unifying these molecules.

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“…The term was coined-as far as we know-a few years before the isolation of AAI (Le Nguyen et al, 1990). As of today there is well-maintained database of knottin structures (knottin dbase) that currently has 3,320 sequences and 214 3D structure entries (Postic et al, 2018) (www. dsimb.inserm.fr/KNOTTIN/).…”

Section: The 3d Structure Of Aaimentioning

confidence: 99%

Structure and Oxidative Folding of AAI, the Major Alfa-Amylase Inhibitor From Amaranth Seeds

2020

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AAI, the major alpha-amylase inhibitor (AAI) present in the seeds of the Mexican crop plant Amaranthus hypocondriacus is a 32-residue-long polypeptide with three disulfide bridges. Its structure is most closely related to the plant amylase inhibitor subfamily of knottins characterized by a topological knot formed by one disulfide bridge threading through a loop formed by the peptide chain as well as a short three-stranded beta sandwich core. AAI is specific against insect amylases and does not act on corresponding human or mammalian enzymes. It was found that the oxidative folding of AAI seems to follow a hirudine-like pathway with many non-native intermediates, but notably it proceeds through a major folding intermediate (MFI) that contains a vicinal disulfide bridge. Based on a review of the pertinent literature, the known vicinal disulfides in native proteins as well as well as the network of disulfide interchanges, we propose that MFI is a kinetic trap corresponding to a compact molten globule-like state which constrains the peptide chain to a smaller number of conformations that in turn can be rapidly funneled toward the native state. AAI: THE MAJOR ALPHA AMYLASE INHIBITOR OF Amaranthus hypochondriacusAAI (amaranth amylase inhibitor) is an alpha-amylase inhibitor isolated from the Mexican crop plant Amaranthus hypochondriacus. Amaranth grains are known to be cultivated for about 8,000 years and were part of the diet of the Aztecs. Today, Amaranth is grown in Mexico, Peru, and Bolivia, but the world's largest producer is China with an estimated annual production of 87 million metric tons. Amaranths are classified as pseudo cereals as they are not in the same botanical family as true cereals to which their grains bear similarity.Aqueous extracts of Amaranth grains were found to inhibit insect alpha-amylases extracted from the larvae of the red flour beetle (Dibolium castaneum) and of the grain borer (Prostephanus truncatus). The alpha-amylase was purified with classical techniques (Chagolla-Lopez et al., 1994). Briefly, crude extracts of amaranth flour were fractionated by ammonium sulfate precipitation (35-65%), fractionated on G75 Sepharose columns and the lyophilized active fractions were subjected to ion exchange chromatography The majority of inhibitory activity was found in one major peak which was further purified with reverse phase HPLC (RP-HPLC). The inhibitory activity was resistant to heat. As amino acid analysis revealed a high percentage of cysteine with no free sulfhydryl groups, the samples were reduced

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KNOTTIN: the database of inhibitor cystine knot scaffold after 10 years, toward a systematic structure modeling

Cited by 92 publications

References 22 publications

Tying pest insects in knots: the deployment of spider‐venom‐derived knottins as bioinsecticides

Tying pest insects in knots: the deployment of spider‐venom‐derived knottins as bioinsecticides

Screening, large-scale production and structure-based classification of cystine-dense peptides

Structure and Oxidative Folding of AAI, the Major Alfa-Amylase Inhibitor From Amaranth Seeds

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