+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-34892 | |||||||||
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タイトル | Cryo-EM structure of human high-voltage activated L-type calcium channel CaV1.2 in complex with benidipine (BEN) | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | ben bound state / MEMBRANE PROTEIN | |||||||||
機能・相同性 | 機能・相同性情報 voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels / positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / positive regulation of high voltage-gated calcium channel activity / membrane depolarization during atrial cardiac muscle cell action potential / Phase 2 - plateau phase / calcium ion transmembrane transport via high voltage-gated calcium channel / positive regulation of muscle contraction / membrane depolarization during AV node cell action potential ...voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels / positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / positive regulation of high voltage-gated calcium channel activity / membrane depolarization during atrial cardiac muscle cell action potential / Phase 2 - plateau phase / calcium ion transmembrane transport via high voltage-gated calcium channel / positive regulation of muscle contraction / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / L-type voltage-gated calcium channel complex / photoreceptor ribbon synapse / cardiac muscle cell action potential involved in contraction / positive regulation of calcium ion transport / NCAM1 interactions / regulation of ventricular cardiac muscle cell membrane repolarization / calcium ion import / calcium ion transport into cytosol / Sensory processing of sound by inner hair cells of the cochlea / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / neuromuscular junction development / calcium ion import across plasma membrane / Phase 0 - rapid depolarisation / neuronal dense core vesicle / regulation of heart rate by cardiac conduction / regulation of calcium ion transport / voltage-gated calcium channel activity / T-tubule / visual perception / sarcoplasmic reticulum / protein localization to plasma membrane / Regulation of insulin secretion / calcium ion transmembrane transport / postsynaptic density membrane / calcium channel activity / Adrenaline,noradrenaline inhibits insulin secretion / cellular response to amyloid-beta / calcium ion transport / actin filament binding / presynapse / chemical synaptic transmission / perikaryon / dendrite / extracellular exosome / metal ion binding / plasma membrane 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.3 Å | |||||||||
データ登録者 | Wei Y / Yu Z / Zhao Y | |||||||||
資金援助 | 中国, 1件
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引用 | ジャーナル: Nat Commun / 年: 2024 タイトル: Structural bases of inhibitory mechanism of Ca1.2 channel inhibitors. 著者: Yiqing Wei / Zhuoya Yu / Lili Wang / Xiaojing Li / Na Li / Qinru Bai / Yuhang Wang / Renjie Li / Yufei Meng / Hao Xu / Xianping Wang / Yanli Dong / Zhuo Huang / Xuejun Cai Zhang / Yan Zhao / 要旨: The voltage-gated calcium channel Ca1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca1.2 are involved ...The voltage-gated calcium channel Ca1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6, S6, and S6 helices and forms extensive hydrophobic interactions with Ca1.2. Our structure elucidates that benidipine is located in the D-D fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5, S6, and S6 helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels. | |||||||||
履歴 |
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-構造の表示
添付画像 |
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-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_34892.map.gz | 118.1 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-34892-v30.xml emd-34892.xml | 20.8 KB 20.8 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_34892_fsc.xml | 10.6 KB | 表示 | FSCデータファイル |
画像 | emd_34892.png | 41.4 KB | ||
Filedesc metadata | emd-34892.cif.gz | 8.5 KB | ||
その他 | emd_34892_half_map_1.map.gz emd_34892_half_map_2.map.gz | 116.1 MB 116.1 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-34892 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-34892 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_34892_validation.pdf.gz | 1010.5 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_34892_full_validation.pdf.gz | 1010 KB | 表示 | |
XML形式データ | emd_34892_validation.xml.gz | 18.7 KB | 表示 | |
CIF形式データ | emd_34892_validation.cif.gz | 23.5 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34892 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34892 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_34892.map.gz / 形式: CCP4 / 大きさ: 125 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.04 Å | ||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-ハーフマップ: #2
ファイル | emd_34892_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_34892_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
-全体 : CaV3.3
全体 | 名称: CaV3.3 |
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要素 |
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-超分子 #1: CaV3.3
超分子 | 名称: CaV3.3 / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
-分子 #1: Isoform 2c of Voltage-dependent L-type calcium channel subunit beta-2
分子 | 名称: Isoform 2c of Voltage-dependent L-type calcium channel subunit beta-2 タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 70.952688 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: MNQGSGLDLL KISYGKGARR KNRFKGSDGS TSSDTTSNSF VRQGSADSYT SRPSDSDVSL EEDREAVRRE AERQAQAQLE KAKTKPVAF AVRTNVSYSA AHEDDVPVPG MAISFEAKDF LHVKEKFNND WWIGRLVKEG CEIGFIPSPV KLENMRLQHE Q RAKQGKFY ...文字列: MNQGSGLDLL KISYGKGARR KNRFKGSDGS TSSDTTSNSF VRQGSADSYT SRPSDSDVSL EEDREAVRRE AERQAQAQLE KAKTKPVAF AVRTNVSYSA AHEDDVPVPG MAISFEAKDF LHVKEKFNND WWIGRLVKEG CEIGFIPSPV KLENMRLQHE Q RAKQGKFY SSKSGGNSSS SLGDIVPSSR KSTPPSSAID IDATGLDAEE NDIPANHRSP KPSANSVTSP HSKEKRMPFF KK TEHTPPY DVVPSMRPVV LVGPSLKGYE VTDMMQKALF DFLKHRFEGR ISITRVTADI SLAKRSVLNN PSKHAIIERS NTR SSLAEV QSEIERIFEL ARTLQLVVLD ADTINHPAQL SKTSLAPIIV YVKISSPKVL QRLIKSRGKS QAKHLNVQMV AADK LAQCP PELFDVILDE NQLEDACEHL ADYLEAYWKA THPPSSSLPN PLLSRTLATS SLPLSPTLAS NSQGSQGDQR TDRSA PIRS ASQAEEEPSV EPVKKSQHRS SSSAPHHNHR SGTSRGLSRQ ETFDSETQES RDSAYVEPKE DYSHDHVDHY ASHRDH NHR DETHGSSDHR HRESRHRSRD VDREQDHNEC NKQRSRHKSK DRYCEKDGEV ISKKRNEAGE WNRDVYIRQ UniProtKB: Voltage-dependent L-type calcium channel subunit beta-2 |
-分子 #2: Voltage-dependent L-type calcium channel subunit alpha
分子 | 名称: Voltage-dependent L-type calcium channel subunit alpha タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 243.947016 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: MVNENTRMYI PEENHQGSNY GSPRPAHANM NANAAAGLAP EHIPTPGAAL SWQAAIDAAR QAKLMGSAGN ATISTVSSTQ RKRQQYGKP KKQGSTTATR PPRALLCLTL KNPIRRACIS IVEWKPFEII ILLTIFANCV ALAIYIPFPE DDSNATNSNL E RVEYLFLI ...文字列: MVNENTRMYI PEENHQGSNY GSPRPAHANM NANAAAGLAP EHIPTPGAAL SWQAAIDAAR QAKLMGSAGN ATISTVSSTQ RKRQQYGKP KKQGSTTATR PPRALLCLTL KNPIRRACIS IVEWKPFEII ILLTIFANCV ALAIYIPFPE DDSNATNSNL E RVEYLFLI IFTVEAFLKV IAYGLLFHPN AYLRNGWNLL DFIIVVVGLF SAILEQATKA DGANALGGKG AGFDVKALRA FR VLRPLRL VSGVPSLQVV LNSIIKAMVP LLHIALLVLF VIIIYAIIGL ELFMGKMHKT CYNQEGIADV PAEDDPSPCA LET GHGRQC QNGTVCKPGW DGPKHGITNF DNFAFAMLTV FQCITMEGWT DVLYWVNDAV GRDWPWIYFV TLIIIGSFFV LNLV LGVLS GEFSKEREKA KARGDFQKLR EKQQLEEDLK GYLDWITQAE DIDPENEDEG MDEEKPRNMS MPTSETESVN TENVA GGDI EGENCGARLA HRISKSKFSR YWRRWNRFCR RKCRAAVKSN VFYWLVIFLV FLNTLTIASE HYNQPNWLTE VQDTAN KAL LALFTAEMLL KMYSLGLQAY FVSLFNRFDC FVVCGGILET ILVETKIMSP LGISVLRCVR LLRIFKITRY WNSLSNL VA SLLNSVRSIA SLLLLLFLFI IIFSLLGMQL FGGKFNFDEM QTRRSTFDNF PQSLLTVFQI LTGEDWNSVM YDGIMAYG G PSFPGMLVCI YFIILFICGN YILLNVFLAI AVDNLADAES LTSAQKEEEE EKERKKLART ASPEKKQELV EKPAVGESK EEKIELKSIT ADGESPPATK INMDDLQPNE NEDKSPYPNP ETTGEEDEEE PEMPVGPRPR PLSELHLKEK AVPMPEASAF FIFSSNNRF RLQCHRIVND TIFTNLILFF ILLSSISLAA EDPVQHTSFR NHILFYFDIV FTTIFTLEII LKMTAYGAFL H KGSFCRNY FNILDLLVVS VSLISFGIQS SAINVVKILR VLRVLRPLRA INRAKGLKHV VQCVFVAIRT IGNIVIVTTL LQ FMFACIG VQLFKGKLYT CSDSSKQTEA ECKGNYITYK DGEVDHPIIQ PRSWENSKFD FDNVLAAMMA LFTVSTFEGW PEL LYRSID SHTEDKGPIY NYRVEISIFF IIYIIIIAFF MMNIFVGFVI VTFQEQGEQE YKNCELDKNQ RQCVEYALKA RPLR RYIPK NQHQYKVWYV VNSTYFEYLM FVLILLNTIC LAMQHYGQSC LFKIAMNILN MLFTGLFTVE MILKLIAFKP KGYFS DPWN VFDFLIVIGS IIDVILSEVN PAEHTQCSPS MNAEENSRIS ITFFRLFRVM RLVKLLSRGE GIRTLLWTFI KSFQAL PYV ALLIVMLFFI YAVIGMQVFG KIALNDTTEI NRNNNFQTFP QAVLLLFRCA TGEAWQDIML ACMPGKKCAP ESEPSNS TE GETPCGSSFA VFYFISFYML CAFLIINLFV AVIMDNFDYL TRDWSILGPH HLDEFKRIWA EYDPEAKGRI KHLDVVTL L RRIQPPLGFG KLCPHRVACK RLVSMNMPLN SDGTVMFNAT LFALVRTALR IKTEGNLEQA NEELRAIIKK IWKRTSMKL LDQVVPPAGD DEVTVGKFYA TFLIQEYFRK FKKRKEQGLV GKPSQRNALS LQAGLRTLHD IGPEIRRAIS GDLTAEEELD KAMKEAVSA ASEDDIFRRA GGLFGNHVSY YQSDGRSAFP QTFTTQRPLH INKAGSSQGD TESPSHEKLV DSTFTPSSYS S TGSNANIN NANNTALGRL PRPAGYPSTV STVEGHGPPL SPAIRVQEVA WKLSSNRERH VPMCEDLELR RDSGSAGTQA HC LLLRRAN PSRCHSRESQ AAMAGQEETS QDETYEVKMN HDTEACSEPS LLSTEMLSYQ DDENRQLTLP EEDKRDIRQS PKR GFLRSA SLGRRASFHL ECLKRQKDRG GDISQKTVLP LHLVHHQALA VAGLSPLLQR SHSPASFPRP FATPPATPGS RGWP PQPVP TLRLEGVESS EKLNSSFPSI HCGSWAETTP GGGGSSAARR VRPVSLMVPS QAGAPGRQFH GSASSLVEAV LISEG LGQF AQDPKFIEVT TQELADACDM TIEEMESAAD NILSGGAPQS PNGALLPFVN CRDAGQDRAG GEEDAGCVRA RGRPSE EEL QDSRVYVSSL UniProtKB: Voltage-dependent L-type calcium channel subunit alpha |
-分子 #3: Voltage-dependent calcium channel subunit alpha-2/delta-1
分子 | 名称: Voltage-dependent calcium channel subunit alpha-2/delta-1 タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
分子量 | 理論値: 121.197406 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: MAAGCLLALT LTLFQSLLIG PSSEEPFPSA VTIKSWVDKM QEDLVTLAKT ASGVNQLVDI YEKYQDLYTV EPNNARQLVE IAARDIEKL LSNRSKALVR LALEAEKVQA AHQWREDFAS NEVVYYNAKD DLDPEKNDSE PGSQRIKPVF IEDANFGRQI S YQHAAVHI ...文字列: MAAGCLLALT LTLFQSLLIG PSSEEPFPSA VTIKSWVDKM QEDLVTLAKT ASGVNQLVDI YEKYQDLYTV EPNNARQLVE IAARDIEKL LSNRSKALVR LALEAEKVQA AHQWREDFAS NEVVYYNAKD DLDPEKNDSE PGSQRIKPVF IEDANFGRQI S YQHAAVHI PTDIYEGSTI VLNELNWTSA LDEVFKKNRE EDPSLLWQVF GSATGLARYY PASPWVDNSR TPNKIDLYDV RR RPWYIQG AASPKDMLIL VDVSGSVSGL TLKLIRTSVS EMLETLSDDD FVNVASFNSN AQDVSCFQHL VQANVRNKKV LKD AVNNIT AKGITDYKKG FSFAFEQLLN YNVSRANCNK IIMLFTDGGE ERAQEIFNKY NKDKKVRVFT FSVGQHNYDR GPIQ WMACE NKGYYYEIPS IGAIRINTQE YLDVLGRPMV LAGDKAKQVQ WTNVYLDALE LGLVITGTLP VFNITGQFEN KTNLK NQLI LGVMGVDVSL EDIKRLTPRF TLCPNGYYFA IDPNGYVLLH PNLQPKPIGV GIPTINLRKR RPNIQNPKSQ EPVTLD FLD AELENDIKVE IRNKMIDGES GEKTFRTLVK SQDERYIDKG NRTYTWTPVN GTDYSLALVL PTYSFYYIKA KLEETIT QA RYSETLKPDN FEESGYTFIA PRDYCNDLKI SDNNTEFLLN FNEFIDRKTP NNPSCNADLI NRVLLDAGFT NELVQNYW S KQKNIKGVKA RFVVTDGGIT RVYPKEAGEN WQENPETYED SFYKRSLDND NYVFTAPYFN KSGPGAYESG IMVSKAVEI YIQGKLLKPA VVGIKIDVNS WIENFTKTSI RDPCAGPVCD CKRNSDVMDC VILDDGGFLL MANHDDYTNQ IGRFFGEIDP SLMRHLVNI SVYAFNKSYD YQSVCEPGAA PKQGAGHRSA YVPSVADILQ IGWWATAAAW SILQQFLLSL TFPRLLEAVE M EDDDFTAS LSKQSCITEQ TQYFFDNDSK SFSGVLDCGN CSRIFHGEKL MNTNLIFIMV ESKGTCPCDT RLLIQAEQTS DG PNPCDMV KQPRYRKGPD VCFDNNVLED YTDC UniProtKB: Voltage-dependent calcium channel subunit alpha-2/delta-1 |
-分子 #4: HEXADECANE
分子 | 名称: HEXADECANE / タイプ: ligand / ID: 4 / コピー数: 8 / 式: R16 |
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分子量 | 理論値: 226.441 Da |
Chemical component information | ChemComp-R16: |
-分子 #5: 1,2-Distearoyl-sn-glycerophosphoethanolamine
分子 | 名称: 1,2-Distearoyl-sn-glycerophosphoethanolamine / タイプ: ligand / ID: 5 / コピー数: 3 / 式: 3PE |
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分子量 | 理論値: 748.065 Da |
Chemical component information | ChemComp-3PE: |
-分子 #6: (3R)-1-benzylpiperidin-3-yl methyl (2R,3R,4R,5R,6S)-2,6-dimethyl-...
分子 | 名称: (3R)-1-benzylpiperidin-3-yl methyl (2R,3R,4R,5R,6S)-2,6-dimethyl-4-(3-nitrophenyl)piperidine-3,5-dicarboxylate タイプ: ligand / ID: 6 / コピー数: 1 / 式: A1AC8 |
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分子量 | 理論値: 506.57 Da |
-分子 #7: CALCIUM ION
分子 | 名称: CALCIUM ION / タイプ: ligand / ID: 7 / コピー数: 2 / 式: CA |
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分子量 | 理論値: 40.078 Da |
-分子 #8: 2-acetamido-2-deoxy-beta-D-glucopyranose
分子 | 名称: 2-acetamido-2-deoxy-beta-D-glucopyranose / タイプ: ligand / ID: 8 / コピー数: 8 / 式: NAG |
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分子量 | 理論値: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 7.5 |
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凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) 平均電子線量: 9.6 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.2 µm / 最小 デフォーカス(公称値): 1.2 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |