8fhs

From Proteopedia

(Difference between revisions)

Revision as of 07:15, 21 November 2024

Human L-type voltage-gated calcium channel Cav1.2 in the presence of amiodarone and sofosbuvir at 3.3 Angstrom resolution

Structural highlights

8fhs is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.3Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CA2D1_HUMAN Familial short QT syndrome;Non-specific early-onset epileptic encephalopathy;Brugada syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

CA2D1_HUMAN The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel (PubMed:35293990). Plays an important role in excitation-contraction coupling (By similarity).^[1]

Publication Abstract from PubMed

Ca(v)1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Ca(v)1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSD(II). Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Na(v) channels, a series of structural changes occur, including upward movement of VSD(II) coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5(III) merges with S5(III) to become a single helix, resulting in a widened but still non-conductive intracellular gate.

Structural basis for human Ca(v)1.2 inhibition by multiple drugs and the neurotoxin calciseptine.,Gao S, Yao X, Chen J, Huang G, Fan X, Xue L, Li Z, Wu T, Zheng Y, Huang J, Jin X, Wang Y, Wang Z, Yu Y, Liu L, Pan X, Song C, Yan N Cell. 2023 Nov 22;186(24):5363-5374.e16. doi: 10.1016/j.cell.2023.10.007. Epub , 2023 Nov 15. PMID:37972591^[2]

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

References

↑ Dahimene S, von Elsner L, Holling T, Mattas LS, Pickard J, Lessel D, Pilch KS, Kadurin I, Pratt WS, Zhulin IB, Dai H, Hempel M, Ruzhnikov MRZ, Kutsche K, Dolphin AC. Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy. Brain. 2022 Aug 27;145(8):2721-2729. PMID:35293990 doi:10.1093/brain/awac081
↑ Gao S, Yao X, Chen J, Huang G, Fan X, Xue L, Li Z, Wu T, Zheng Y, Huang J, Jin X, Wang Y, Wang Z, Yu Y, Liu L, Pan X, Song C, Yan N. Structural basis for human Ca(v)1.2 inhibition by multiple drugs and the neurotoxin calciseptine. Cell. 2023 Nov 22;186(24):5363-5374.e16. PMID:37972591 doi:10.1016/j.cell.2023.10.007

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8fhs"

Categories: Homo sapiens | Large Structures | Gao S | Yan N | Yao X

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[8fhs]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FHS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FHS FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.3&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3PE:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>3PE</scene>, <scene name='pdbligand=BBI:(2-BUTYL-1-BENZOFURAN-3-YL){4-[2-(DIETHYLAMINO)ETHOXY]-3,5-DIIODOPHENYL}METHANONE'>BBI</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=WG6:Sofosbuvir'>WG6</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3PE:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>3PE</scene>, <scene name='pdbligand=BBI:(2-BUTYL-1-BENZOFURAN-3-YL){4-[2-(DIETHYLAMINO)ETHOXY]-3,5-DIIODOPHENYL}METHANONE'>BBI</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=WG6:propan-2-yl+(2~{S})-2-[[[(2~{R},3~{R},4~{R},5~{R})-5-[2,4-bis(oxidanylidene)pyrimidin-1-yl]-4-fluoranyl-4-methyl-3-oxidanyl-oxolan-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate'>WG6</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=8fhs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fhs OCA], [https://pdbe.org/8fhs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fhs RCSB], [https://www.ebi.ac.uk/pdbsum/8fhs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fhs ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[https://www.uniprot.org/uniprot/CAC1C_HUMAN CAC1C_HUMAN] Defects in CACNA1C are the cause of Timothy syndrome (TS) [MIM:[https://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:[https://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>
+[https://www.uniprot.org/uniprot/CA2D1_HUMAN CA2D1_HUMAN] Familial short QT syndrome;Non-specific early-onset epileptic encephalopathy;Brugada syndrome. The disease is caused by variants affecting the gene represented in this entry.
 == Function ==
-[https://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>
+[https://www.uniprot.org/uniprot/CA2D1_HUMAN CA2D1_HUMAN] The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel (PubMed:35293990). Plays an important role in excitation-contraction coupling (By similarity).<ref>PMID:35293990</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

8fhs

From Proteopedia

Revision as of 07:15, 21 November 2024

Human L-type voltage-gated calcium channel Cav1.2 in the presence of amiodarone and sofosbuvir at 3.3 Angstrom resolution

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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