4MA8

Structural basis of prion inhibition by phenothiazine compounds.

(2014) Structure 22: 291-303

• PubMed: 24373770 Search on PubMed
• DOI: https://doi.org/10.1016/j.str.2013.11.009
• Primary Citation of Related Structures:  
  4MA7, 4MA8


• PubMed 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.

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Organizational Affiliation: 

Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.