4MA7

Crystal structure of mouse prion protein complexed with Promazine

4MA7 の概要

• エントリーDOI: 10.2210/pdb4ma7/pdb
• 関連するPDBエントリー: 4MA8
• 分子名称: Major prion protein, POM1 heavy chain, POM1 light chain, ... (5 entities in total)
• 機能のキーワード: immunoglobulin fold, fab, antibody, mouse prion protein, immune system
• 由来する生物種: Mus musculus (mouse); 詳細
• 細胞内の位置: Cell membrane; Lipid-anchor, GPI-anchor (By similarity): P04925
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 60552.08

構造登録者

Baral, P.K.,Swayampakula, M.,James, M.N.G. (登録日: 2013-08-15, 公開日: 2014-01-22, 最終更新日: 2024-11-27)

主引用文献

Baral, P.K.,Swayampakula, M.,Rout, M.K.,Kav, N.N.,Spyracopoulos, L.,Aguzzi, A.,James, M.N.
Structural basis of prion inhibition by phenothiazine compounds.
Structure, 22:291-303, 2014

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.

PubMed: 24373770
DOI: 10.1016/j.str.2013.11.009

実験手法

X-RAY DIFFRACTION (1.97 Å)