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| | <StructureSection load='5aan' size='340' side='right'caption='[[5aan]], [[Resolution|resolution]] 1.60Å' scene=''> | | <StructureSection load='5aan' size='340' side='right'caption='[[5aan]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5aan]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Drome Drome]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AAN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AAN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5aan]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AAN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AAN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PG0:2-(2-METHOXYETHOXY)ETHANOL'>PG0</scene>, <scene name='pdbligand=XOC:N-PHENOTHIAZIN-10-YL-2-PIPERIDIN-1-YL-ETHANAMIDE'>XOC</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PG0:2-(2-METHOXYETHOXY)ETHANOL'>PG0</scene>, <scene name='pdbligand=XOC:N-PHENOTHIAZIN-10-YL-2-PIPERIDIN-1-YL-ETHANAMIDE'>XOC</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5aan FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aan OCA], [http://pdbe.org/5aan PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5aan RCSB], [http://www.ebi.ac.uk/pdbsum/5aan PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5aan ProSAT]</span></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=5aan FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aan OCA], [https://pdbe.org/5aan PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aan RCSB], [https://www.ebi.ac.uk/pdbsum/5aan PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aan ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/Q9VWX8_DROME Q9VWX8_DROME] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Drome]] | + | [[Category: Drosophila melanogaster]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Chaves-Sanjuan, A]] | + | [[Category: Chaves-Sanjuan A]] |
| - | [[Category: Infantes, L]] | + | [[Category: Infantes L]] |
| - | [[Category: Sanchez-Barrena, M J]] | + | [[Category: Sanchez-Barrena MJ]] |
| - | [[Category: Calcium sensor]]
| + | |
| - | [[Category: Calcium-binding protein]]
| + | |
| Structural highlights
Function
Q9VWX8_DROME
Publication Abstract from PubMed
The protein complex formed by the Ca2+ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-1. The crystal structure of NCS-1 bound to FD44 and the structure-function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.
Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome.,Mansilla A, Chaves-Sanjuan A, Campillo NE, Semelidou O, Martinez-Gonzalez L, Infantes L, Gonzalez-Rubio JM, Gil C, Conde S, Skoulakis EM, Ferrus A, Martinez A, Sanchez-Barrena MJ Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):E999-E1008. doi:, 10.1073/pnas.1611089114. Epub 2017 Jan 24. PMID:28119500[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mansilla A, Chaves-Sanjuan A, Campillo NE, Semelidou O, Martinez-Gonzalez L, Infantes L, Gonzalez-Rubio JM, Gil C, Conde S, Skoulakis EM, Ferrus A, Martinez A, Sanchez-Barrena MJ. Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome. Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):E999-E1008. doi:, 10.1073/pnas.1611089114. Epub 2017 Jan 24. PMID:28119500 doi:http://dx.doi.org/10.1073/pnas.1611089114
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