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- PDB-8e58: Rabbit L-type voltage-gated calcium channel Cav1.1 in the presenc... -

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基本情報

登録情報
データベース: PDB / ID: 8.0E+58
タイトルRabbit L-type voltage-gated calcium channel Cav1.1 in the presence of Amiodarone and 1 mM MNI-1 at 3.0 Angstrom resolution
要素
  • (Voltage-dependent calcium channel ...) x 2
  • Voltage-dependent L-type calcium channel subunit alpha-1S
キーワードTRANSPORT PROTEIN / Cav1.1 / Channels / Calcium Ion-Selective
機能・相同性
機能・相同性情報


positive regulation of muscle contraction / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / cellular response to caffeine / calcium channel regulator activity / calcium ion import across plasma membrane / voltage-gated calcium channel activity / release of sequestered calcium ion into cytosol / regulation of ryanodine-sensitive calcium-release channel activity ...positive regulation of muscle contraction / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / cellular response to caffeine / calcium channel regulator activity / calcium ion import across plasma membrane / voltage-gated calcium channel activity / release of sequestered calcium ion into cytosol / regulation of ryanodine-sensitive calcium-release channel activity / T-tubule / muscle contraction / calcium ion transmembrane transport / sarcolemma / transmembrane transporter binding / calmodulin binding / metal ion binding / plasma membrane
類似検索 - 分子機能
Voltage-dependent calcium channel, gamma-1 subunit / Voltage-dependent calcium channel, L-type, alpha-1S subunit / PMP-22/EMP/MP20/Claudin tight junction / Voltage-gated calcium channel subunit alpha, C-terminal / Voltage-gated calcium channel subunit alpha, C-term / Voltage-dependent calcium channel, L-type, alpha-1 subunit / VWA N-terminal / Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / VWA N-terminal / Neuronal voltage-dependent calcium channel alpha 2acd ...Voltage-dependent calcium channel, gamma-1 subunit / Voltage-dependent calcium channel, L-type, alpha-1S subunit / PMP-22/EMP/MP20/Claudin tight junction / Voltage-gated calcium channel subunit alpha, C-terminal / Voltage-gated calcium channel subunit alpha, C-term / Voltage-dependent calcium channel, L-type, alpha-1 subunit / VWA N-terminal / Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / VWA N-terminal / Neuronal voltage-dependent calcium channel alpha 2acd / Voltage-dependent calcium channel, alpha-1 subunit, IQ domain / Voltage gated calcium channel IQ domain / Voltage gated calcium channel IQ domain / Voltage-dependent calcium channel, alpha-1 subunit / Voltage-dependent L-type calcium channel, IQ-associated domain / Voltage-dependent L-type calcium channel, IQ-associated / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / von Willebrand factor type A domain / von Willebrand factor (vWF) type A domain / VWFA domain profile. / Voltage-dependent channel domain superfamily / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / Ion transport domain / Ion transport protein
類似検索 - ドメイン・相同性
triacetyl-beta-chitotriose / Chem-BBI / Chem-WFR / Voltage-dependent L-type calcium channel subunit alpha-1S / Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-dependent calcium channel gamma-1 subunit
類似検索 - 構成要素
生物種Oryctolagus cuniculus (ウサギ)
手法電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3 Å
データ登録者Gao, S. / Yao, X. / Yan, N.
資金援助 米国, 1件
組織認可番号国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5R01GM130762 米国
引用ジャーナル: Cell / 年: 2022
タイトル: Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Ca channels.
著者: Xia Yao / Shuai Gao / Jixin Wang / Zhangqiang Li / Jian Huang / Yan Wang / Zhifei Wang / Jiaofeng Chen / Xiao Fan / Weipeng Wang / Xueqin Jin / Xiaojing Pan / Yong Yu / Armando Lagrutta / Nieng Yan /
要旨: Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate ...Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Ca channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Ca1.1 and Ca1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone. Whereas amiodarone alone occupies the dihydropyridine binding site, sofosbuvir is not found in the channel when applied on its own. In the presence of amiodarone, sofosbuvir/MNI-1 is anchored in the central cavity of the pore domain through specific interaction with amiodarone and directly obstructs the ion permeation path. Our study reveals the molecular basis for the physical, pharmacodynamic interaction of two drugs on the scaffold of Ca channels.
履歴
登録2022年8月20日登録サイト: RCSB / 処理サイト: RCSB
改定 1.02022年12月7日Provider: repository / タイプ: Initial release
改定 1.12022年12月21日Group: Database references / カテゴリ: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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構造の表示

構造ビューア分子:
MolmilJmol/JSmol

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集合体

登録構造単位
A: Voltage-dependent L-type calcium channel subunit alpha-1S
E: Voltage-dependent calcium channel gamma-1 subunit
F: Voltage-dependent calcium channel subunit alpha-2/delta-1
ヘテロ分子


分子量 (理論値)分子数
合計 (水以外)368,80121
ポリマ－362,4933
非ポリマー6,30818
水00
1


  • 登録構造と同一
  • 登録者が定義した集合体
  • 根拠: gel filtration
タイプ名称対称操作数
identity operation1_5551

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要素

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タンパク質 , 1種, 1分子 A

#1: タンパク質 Voltage-dependent L-type calcium channel subunit alpha-1S / Calcium channel / L type / alpha-1 polypeptide / isoform 3 / skeletal muscle / Dihydropyridine ...Calcium channel / L type / alpha-1 polypeptide / isoform 3 / skeletal muscle / Dihydropyridine receptor alpha-1S subunit / DHPR / Voltage-gated calcium channel subunit alpha Cav1.1


分子量: 212240.594 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) Oryctolagus cuniculus (ウサギ) / 参照: UniProt: P07293

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Voltage-dependent calcium channel ... , 2種, 2分子 EF

#2: タンパク質 Voltage-dependent calcium channel gamma-1 subunit / Dihydropyridine-sensitive L-type / skeletal muscle calcium channel subunit gamma


分子量: 25082.254 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) Oryctolagus cuniculus (ウサギ) / 参照: UniProt: P19518
#3: タンパク質 Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-gated calcium channel subunit alpha-2/delta-1


分子量: 125169.984 Da / 分子数: 1 / 由来タイプ: 天然 / 由来: (天然) Oryctolagus cuniculus (ウサギ) / 参照: UniProt: P13806

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糖 , 4種, 14分子

#4: 多糖
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


タイプ: oligosaccharide / 分子量: 424.401 Da / 分子数: 4 / 由来タイプ: 組換発現
記述子タイププログラム
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: 多糖 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


タイプ: oligosaccharide, Oligosaccharide / クラス: 阻害剤 / 分子量: 627.594 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: oligosaccharide / 参照: triacetyl-beta-chitotriose
記述子タイププログラム
DGlcpNAcb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,3,2/[a2122h-1b_1-5_2*NCC/3=O]/1-1-1/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: 多糖 beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose