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PDBsum entry 2mgo
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References listed in PDB file
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Key reference
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Title
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Oxytocic plant cyclotides as templates for peptide g protein-Coupled receptor ligand design.
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Authors
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J.Koehbach,
M.O'Brien,
M.Muttenthaler,
M.Miazzo,
M.Akcan,
A.G.Elliott,
N.L.Daly,
P.J.Harvey,
S.Arrowsmith,
S.Gunasekera,
T.J.Smith,
S.Wray,
U.Göransson,
P.E.Dawson,
D.J.Craik,
M.Freissmuth,
C.W.Gruber.
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Ref.
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Proc Natl Acad Sci U S A, 2013,
110,
21183-21188.
[DOI no: ]
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PubMed id
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Abstract
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Cyclotides are plant peptides comprising a circular backbone and three conserved
disulfide bonds that confer them with exceptional stability. They were
originally discovered in Oldenlandia affinis based on their use in traditional
African medicine to accelerate labor. Recently, cyclotides have been identified
in numerous plant species of the coffee, violet, cucurbit, pea, potato, and
grass families. Their unique structural topology, high stability, and tolerance
to sequence variation make them promising templates for the development of
peptide-based pharmaceuticals. However, the mechanisms underlying their
biological activities remain largely unknown; specifically, a receptor for a
native cyclotide has not been reported hitherto. Using bioactivity-guided
fractionation of an herbal peptide extract known to indigenous healers as
"kalata-kalata," the cyclotide kalata B7 was found to induce strong
contractility on human uterine smooth muscle cells. Radioligand displacement and
second messenger-based reporter assays confirmed the oxytocin and vasopressin
V1a receptors, members of the G protein-coupled receptor family, as molecular
targets for this cyclotide. Furthermore, we show that cyclotides can serve as
templates for the design of selective G protein-coupled receptor ligands by
generating an oxytocin-like peptide with nanomolar affinity. This nonapeptide
elicited dose-dependent contractions on human myometrium. These observations
provide a proof of concept for the development of cyclotide-based peptide
ligands.
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Headers
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