5g08: Difference between revisions
New page: '''Unreleased structure''' The entry 5g08 is ON HOLD until Paper Publication Authors: Chaves-Sanjuan, A., Infantes, L., Sanchez-Barrena, M.J. Description: Crystal structure of Frq boun... |
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==Crystal structure of Drosophila NCS-1 bound to chlorpromazine== | |||
<StructureSection load='5g08' size='340' side='right'caption='[[5g08]], [[Resolution|resolution]] 1.52Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5g08]] 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=5G08 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5G08 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.52Å</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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <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=5g08 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g08 OCA], [https://pdbe.org/5g08 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5g08 RCSB], [https://www.ebi.ac.uk/pdbsum/5g08 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5g08 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q9VWX8_DROME Q9VWX8_DROME] | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:28119500</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5g08" style="background-color:#fffaf0;"></div> | ||
[[Category: Chaves-Sanjuan | == References == | ||
[[Category: Infantes | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Drosophila melanogaster]] | |||
[[Category: Large Structures]] | |||
[[Category: Chaves-Sanjuan A]] | |||
[[Category: Infantes L]] | |||
[[Category: Sanchez-Barrena MJ]] | |||
Latest revision as of 14:50, 1 February 2024
Crystal structure of Drosophila NCS-1 bound to chlorpromazineCrystal structure of Drosophila NCS-1 bound to chlorpromazine
Structural highlights
FunctionPublication Abstract from PubMedThe 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
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