Structural basis of prion inhibition by phenothiazine compounds

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Chlorpromazine / chemistry
  • Mice
  • Molecular Dynamics Simulation
  • Phenothiazines / chemistry*
  • Prions / chemistry*
  • Promazine / chemistry
  • Protein Binding
  • Protein Denaturation
  • Protein Folding
  • Protein Isoforms / chemistry
  • Protein Structure, Secondary
  • Protein Structure, Tertiary

Substances

  • Phenothiazines
  • Prions
  • Protein Isoforms
  • phenothiazine
  • Promazine
  • Chlorpromazine