4ma8

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of mouse prion protein complexed with Chlorpromazine

Structural highlights

4ma8 is a 3 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:
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.^[1] ^[2] ^[3] ^[4]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Mani K, Cheng F, Havsmark B, Jonsson M, Belting M, Fransson LA. Prion, amyloid beta-derived Cu(II) ions, or free Zn(II) ions support S-nitroso-dependent autocleavage of glypican-1 heparan sulfate. J Biol Chem. 2003 Oct 3;278(40):38956-65. Epub 2003 May 5. PMID:12732622 doi:10.1074/jbc.M300394200
↑ Steele AD, Emsley JG, Ozdinler PH, Lindquist S, Macklis JD. Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3416-21. Epub 2006 Feb 21. PMID:16492732 doi:10.1073/pnas.0511290103
↑ Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009 Feb 26;457(7233):1128-32. doi: 10.1038/nature07761. PMID:19242475 doi:10.1038/nature07761
↑ Singh A, Kong Q, Luo X, Petersen RB, Meyerson H, Singh N. Prion protein (PrP) knock-out mice show altered iron metabolism: a functional role for PrP in iron uptake and transport. PLoS One. 2009 Jul 1;4(7):e6115. doi: 10.1371/journal.pone.0006115. PMID:19568430 doi:10.1371/journal.pone.0006115
↑ Baral PK, Swayampakula M, Rout MK, Kav NN, Spyracopoulos L, Aguzzi A, James MN. Structural Basis of Prion Inhibition by Phenothiazine Compounds. Structure. 2013 Dec 24. pii: S0969-2126(13)00459-0. doi:, 10.1016/j.str.2013.11.009. PMID:24373770 doi:http://dx.doi.org/10.1016/j.str.2013.11.009

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4ma8"

Categories: Large Structures | Mus musculus | Baral PK | James MNG | Swayampakula M

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4ma8]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MA8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MA8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Z80:3-(2-CHLORO-10H-PHENOTHIAZIN-10-YL)-N,N-DIMETHYLPROPAN-1-AMINE'>Z80</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Z80:3-(2-CHLORO-10H-PHENOTHIAZIN-10-YL)-N,N-DIMETHYLPROPAN-1-AMINE'>Z80</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ma8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ma8 OCA], [https://pdbe.org/4ma8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ma8 RCSB], [https://www.ebi.ac.uk/pdbsum/4ma8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ma8 ProSAT]</span></td></tr>
 </table>

4ma8

From Proteopedia

Current revision

Crystal structure of mouse prion protein complexed with Chlorpromazine

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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