5v2p
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==CaV beta2a subunit: CaV1.2 AID-CAP complex== | |
| + | <StructureSection load='5v2p' size='340' side='right' caption='[[5v2p]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5v2p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V2P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V2P FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=8VY:1,3-bis(bromomethyl)benzene'>8VY</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v2q|5v2q]]</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=5v2p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v2p OCA], [http://pdbe.org/5v2p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v2p RCSB], [http://www.ebi.ac.uk/pdbsum/5v2p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v2p ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/CAC1C_HUMAN CAC1C_HUMAN]] Defects in CACNA1C are the cause of Timothy syndrome (TS) [MIM:[http://omim.org/entry/601005 601005]]. TS is a disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism.<ref>PMID:15454078</ref> <ref>PMID:15863612</ref> Defects in CACNA1C are the cause of Brugada syndrome type 3 (BRGDA3) [MIM:[http://omim.org/entry/611875 611875]]. A heart disease characterized by the association of Brugada syndrome with shortened QT intervals. Brugada syndrome is a tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not reset.<ref>PMID:17224476</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/CACB2_RAT CACB2_RAT]] The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting (By similarity).<ref>PMID:1370480</ref> <ref>PMID:11604404</ref> <ref>PMID:12042350</ref> [[http://www.uniprot.org/uniprot/CAC1C_HUMAN CAC1C_HUMAN]] Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds. Binding of calmodulin or CABP1 at the same regulatory sites results in an opposit effects on the channel function.<ref>PMID:8392192</ref> <ref>PMID:7737988</ref> <ref>PMID:9013606</ref> <ref>PMID:9607315</ref> <ref>PMID:12176756</ref> <ref>PMID:17071743</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | For many voltage-gated ion channels (VGICs), creation of a properly functioning ion channel requires the formation of specific protein-protein interactions between the transmembrane pore-forming subunits and cystoplasmic accessory subunits. Despite the importance of such protein-protein interactions in VGIC function and assembly, their potential as sites for VGIC modulator development has been largely overlooked. Here, we develop meta-xylyl (m-xylyl) stapled peptides that target a prototypic VGIC high affinity protein-protein interaction, the interaction between the voltage-gated calcium channel (CaV) pore-forming subunit alpha-interaction domain (AID) and cytoplasmic beta-subunit (CaVbeta). We show using circular dichroism spectroscopy, X-ray crystallography, and isothermal titration calorimetry that the m-xylyl staples enhance AID helix formation are structurally compatible with native-like AID:CaVbeta interactions and reduce the entropic penalty associated with AID binding to CaVbeta. Importantly, electrophysiological studies reveal that stapled AID peptides act as effective inhibitors of the CaValpha1:CaVbeta interaction that modulate CaV function in an CaVbeta isoform-selective manner. Together, our studies provide a proof-of-concept demonstration of the use of protein-protein interaction inhibitors to control VGIC function and point to strategies for improved AID-based CaV modulator design. | ||
| - | + | Stapled Voltage-Gated Calcium Channel (CaV) alpha-Interaction Domain (AID) Peptides Act As Selective Protein-Protein Interaction Inhibitors of CaV Function.,Findeisen F, Campiglio M, Jo H, Abderemane-Ali F, Rumpf CH, Pope L, Rossen ND, Flucher BE, DeGrado WF, Minor DL Jr ACS Chem Neurosci. 2017 Jun 21;8(6):1313-1326. doi: 10.1021/acschemneuro.6b00454., Epub 2017 Mar 17. PMID:28278376<ref>PMID:28278376</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 5v2p" style="background-color:#fffaf0;"></div> | |
| - | + | == References == | |
| - | + | <references/> | |
| - | + | __TOC__ | |
| - | + | </StructureSection> | |
[[Category: Campiglio, M]] | [[Category: Campiglio, M]] | ||
| + | [[Category: Degrado, W F]] | ||
| + | [[Category: Findeisen, F]] | ||
[[Category: Flucher, B]] | [[Category: Flucher, B]] | ||
[[Category: Jo, H]] | [[Category: Jo, H]] | ||
| + | [[Category: Minor, D L]] | ||
| + | [[Category: Pope, L]] | ||
| + | [[Category: Rumpf, C H]] | ||
| + | [[Category: Calcium]] | ||
| + | [[Category: Ion channel]] | ||
| + | [[Category: Signaling]] | ||
| + | [[Category: Transport protein]] | ||
Revision as of 11:10, 24 August 2017
CaV beta2a subunit: CaV1.2 AID-CAP complex
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Categories: Campiglio, M | Degrado, W F | Findeisen, F | Flucher, B | Jo, H | Minor, D L | Pope, L | Rumpf, C H | Calcium | Ion channel | Signaling | Transport protein
