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Structure. 2014 Feb 4;22(2):291-303. doi: 10.1016/j.str.2013.11.009. Epub 2013 Dec 26.

Structural basis of prion inhibition by phenothiazine compounds.

Author information

1
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
2
Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada.
3
Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Zurich 8091, Switzerland.
4
Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada. Electronic address: michael.james@ualberta.ca.

Abstract

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.

PMID:
24373770
DOI:
10.1016/j.str.2013.11.009
[Indexed for MEDLINE]
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