4ma8

Crystal structure of mouse prion protein complexed with Chlorpromazine

spinqualitylabelsall models 4ma8, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ma8 is a 3 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: Z80 Related: 4ma7 Gene: Prnp, Prn-p, Prp (LK3 transgenic mice) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [PRIO_MOUSE] Note=Found in high quantity in the brain of humans and animals infected with degenerative neurological diseases such as kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler syndrome (GSS), scrapie, bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy (TME), etc. Function [PRIO_MOUSE] May play a role in neuronal development and synaptic plasticity. May be required for neuronal myelin sheath maintenance. May play a role in iron uptake and iron homeostasis. Soluble oligomers are toxic to cultured neuroblastoma cells and induce apoptosis (in vitro) (By similarity). Association with GPC1 (via its heparan sulfate chains) targets PRNP to lipid rafts. Also provides Cu(2+) or ZN(2+) for the ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate side chains. Publication Abstract from PubMed Conformational transitions of the cellular form of the prion protein, PrPC, into an infectious isoform, PrPSc, 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 PrPSc 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 beta1, 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 alpha2, the alpha2-alpha3 loop, as well as the polymorphic beta2-alpha2 loop. Hence, the stabilization effects of the phenothiazine derivatives on initiator-motifs induce a PrPC isoform that potentially resists oligomerization. Structural Basis of Prion Inhibition by Phenothiazine Compounds.,Baral PK, Swayampakula M, Rout MK, Kav NN, Spyracopoulos L, Aguzzi A, James MN Structure. 2013 Dec 24. pii: S0969-2126(13)00459-0. doi:, 10.1016/j.str.2013.11.009. PMID:24373770 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Prion

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