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PDBsum entry 4ma8
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Immune system
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PDB id
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4ma8
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Contents |
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108 a.a.
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218 a.a.
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213 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural basis of prion inhibition by phenothiazine compounds.
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Authors
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P.K.Baral,
M.Swayampakula,
M.K.Rout,
N.N.Kav,
L.Spyracopoulos,
A.Aguzzi,
M.N.James.
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Ref.
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Structure, 2014,
22,
291-303.
[DOI no: ]
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PubMed id
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Abstract
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Conformational transitions of the cellular form of the prion protein, PrP(C),
into an infectious isoform, PrP(Sc), are considered to be central events in the
progression of fatal neurodegenerative diseases known as transmissible
spongiform encephalopathies. Tricyclic phenothiazine compounds exhibit antiprion
activity; however, the underlying molecular mechanism of PrP(Sc) inhibition
remains elusive. We report the molecular structures of two phenothiazine
compounds, promazine and chlorpromazine bound to a binding pocket formed at the
intersection of the structured and the unstructured domains of the mouse prion
protein. Promazine binding induces structural rearrangement of the unstructured
region proximal to β1, through the formation of a "hydrophobic
anchor." We demonstrate that these molecules, promazine in particular,
allosterically stabilize the misfolding initiator-motifs such as the C terminus
of α2, the α2-α3 loop, as well as the polymorphic β2-α2 loop. Hence, the
stabilization effects of the phenothiazine derivatives on initiator-motifs
induce a PrP(C) isoform that potentially resists oligomerization.
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