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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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PDB id:
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Immune system
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Title:
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Crystal structure of mouse prion protein complexed with chlorpromazine
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Structure:
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Major prion protein. Chain: c. Fragment: unp residues 116-229. Synonym: prp, prp27-30, prp33-35c. Engineered: yes. Pom1 heavy chain. Chain: h. Fragment: fab. Engineered: yes.
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Source:
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Mus musculus. Mouse. Organism_taxid: 10090. Gene: prnp, prn-p, prp. Expressed in: escherichia coli. Expression_system_taxid: 562. Cell: hybridoma. Cell: hybridoma
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Resolution:
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2.20Å
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R-factor:
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0.197
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R-free:
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0.236
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Authors:
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P.K.Baral,M.Swayampakula,M.N.G.James
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Key ref:
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P.K.Baral
et al.
(2014).
Structural basis of prion inhibition by phenothiazine compounds.
Structure,
22,
291-303.
PubMed id:
DOI:
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Date:
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15-Aug-13
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Release date:
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22-Jan-14
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PROCHECK
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Headers
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References
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P04925
(PRIO_MOUSE) -
Major prion protein from Mus musculus
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Seq:
Struc:
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254 a.a.
108 a.a.
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DOI no:
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Structure
22:291-303
(2014)
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PubMed id:
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Structural basis of prion inhibition by phenothiazine compounds.
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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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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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Links
