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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Cryo-EM structure of human NaV1.7/beta1/beta2-TCN-1752 | |||||||||
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機能・相同性 | ![]() corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in Purkinje myocyte action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / node of Ranvier / cardiac muscle cell action potential involved in contraction / regulation of ventricular cardiac muscle cell membrane repolarization / membrane depolarization during action potential / voltage-gated sodium channel complex / locomotion / sodium channel inhibitor activity / neuronal action potential propagation / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / sodium ion transport / behavioral response to pain / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / detection of temperature stimulus involved in sensory perception of pain / membrane depolarization / intercalated disc / sodium ion transmembrane transport / sodium channel regulator activity / neuronal action potential / cardiac muscle contraction / sensory perception of pain / T-tubule / post-embryonic development / axon guidance / response to toxic substance / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of neuron projection development / circadian rhythm / nervous system development / gene expression / response to heat / chemical synaptic transmission / perikaryon / transmembrane transporter binding / cell adhesion / inflammatory response / axon / synapse / extracellular region / plasma membrane 類似検索 - 分子機能 | |||||||||
生物種 | ![]() ![]() ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.09 Å | |||||||||
![]() | Jiang DH / Zhang JT | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural basis for Na1.7 inhibition by pore blockers. 著者: Jiangtao Zhang / Yiqiang Shi / Zhuo Huang / Yue Li / Bei Yang / Jianke Gong / Daohua Jiang / ![]() 要旨: Voltage-gated sodium channel Na1.7 plays essential roles in pain and odor perception. Na1.7 variants cause pain disorders. Accordingly, Na1.7 has elicited extensive attention in developing new ...Voltage-gated sodium channel Na1.7 plays essential roles in pain and odor perception. Na1.7 variants cause pain disorders. Accordingly, Na1.7 has elicited extensive attention in developing new analgesics. Here we present cryo-EM structures of human Na1.7/β1/β2 complexed with inhibitors XEN907, TC-N1752 and Na1.7-IN2, explaining specific binding sites and modulation mechanism for the pore blockers. These inhibitors bind in the central cavity blocking ion permeation, but engage different parts of the cavity wall. XEN907 directly causes α- to π-helix transition of DIV-S6 helix, which tightens the fast inactivation gate. TC-N1752 induces π-helix transition of DII-S6 helix mediated by a conserved asparagine on DIII-S6, which closes the activation gate. Na1.7-IN2 serves as a pore blocker without causing conformational change. Electrophysiological results demonstrate that XEN907 and TC-N1752 stabilize Na1.7 in inactivated state and delay the recovery from inactivation. Our results provide structural framework for Na1.7 modulation by pore blockers, and important implications for developing subtype-selective analgesics. | |||||||||
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構造の表示
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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 | ![]() | 59.5 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 18.6 KB 18.6 KB | 表示 表示 | ![]() |
画像 | ![]() | 49.4 KB | ||
その他 | ![]() ![]() | 59.3 MB 59.3 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-検証レポート
文書・要旨 | ![]() | 717.2 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 716.8 KB | 表示 | |
XML形式データ | ![]() | 12.4 KB | 表示 | |
CIF形式データ | ![]() | 14.3 KB | 表示 | |
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-関連構造データ
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リンク
EMDBのページ | ![]() ![]() |
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||
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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: #1
ファイル | emd_33296_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: #2
ファイル | emd_33296_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 |
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試料の構成要素
-全体 : Sodium channel
全体 | 名称: Sodium channel |
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要素 |
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-超分子 #1: Sodium channel
超分子 | 名称: Sodium channel / タイプ: complex / ID: 1 / キメラ: Yes / 親要素: 0 / 含まれる分子: #1-#3 |
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由来(天然) | 生物種: ![]() |
-分子 #1: Isoform 3 of Sodium channel protein type 9 subunit alpha,Green fl...
分子 | 名称: Isoform 3 of Sodium channel protein type 9 subunit alpha,Green fluorescent protein タイプ: protein_or_peptide / ID: 1 詳細: The fusion protein of Sodium channel, linker, GFP, and tag コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 255.679906 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MAMLPPPGPQ SFVHFTKQSL ALIEQRIAER KSKEPKEEKK DDDEEAPKPS SDLEAGKQLP FIYGDIPPGM VSEPLEDLDP YYADKKTFI VLNKGKTIFR FNATPALYML SPFSPLRRIS IKILVHSLFS MLIMCTILTN CIFMTMNNPP DWTKNVEYTF T GIYTFESL ...文字列: MAMLPPPGPQ SFVHFTKQSL ALIEQRIAER KSKEPKEEKK DDDEEAPKPS SDLEAGKQLP FIYGDIPPGM VSEPLEDLDP YYADKKTFI VLNKGKTIFR FNATPALYML SPFSPLRRIS IKILVHSLFS MLIMCTILTN CIFMTMNNPP DWTKNVEYTF T GIYTFESL VKILARGFCV GEFTFLRDPW NWLDFVVIVF AYLTEFVNLG NVSALRTFRV LRALKTISVI PGLKTIVGAL IQ SVKKLSD VMILTVFCLS VFALIGLQLF MGNLKHKCFR NSLENNETLE SIMNTLESEE DFRKYFYYLE GSKDALLCGF STD SGQCPE GYTCVKIGRN PDYGYTSFDT FSWAFLALFR LMTQDYWENL YQQTLRAAGK TYMIFFVVVI FLGSFYLINL ILAV VAMAY EEQNQANIEE AKQKELEFQQ MLDRLKKEQE EAEAIAAAAA EYTSIRRSRI MGLSESSSET SKLSSKSAKE RRNRR KKKN QKKLSSGEEK GDAEKLSKSE SEDSIRRKSF HLGVEGHRRA HEKRLSTPNQ SPLSIRGSLF SARRSSRTSL FSFKGR GRD IGSETEFADD EHSIFGDNES RRGSLFVPHR PQERRSSNIS QASRSPPMLP VNGKMHSAVD CNGVVSLVDG RSALMLP NG QLLPEGTTNQ IHKKRRCSSY LLSEDMLNDP NLRQRAMSRA SILTNTVEEL EESRQKCPPW WYRFAHKFLI WNCSPYWI K FKKCIYFIVM DPFVDLAITI CIVLNTLFMA MEHHPMTEEF KNVLAIGNLV FTGIFAAEMV LKLIAMDPYE YFQVGWNIF DSLIVTLSLV ELFLADVEGL SVLRSFRLLR VFKLAKSWPT LNMLIKIIGN SVGALGNLTL VLAIIVFIFA VVGMQLFGKS YKECVCKIN DDCTLPRWHM NDFFHSFLIV FRVLCGEWIE TMWDCMEVAG QAMCLIVYMM VMVIGNLVVL NLFLALLLSS F SSDNLTAI EEDPDANNLQ IAVTRIKKGI NYVKQTLREF ILKAFSKKPK ISREIRQAED LNTKKENYIS NHTLAEMSKG HN FLKEKDK ISGFGSSVDK HLMEDSDGQS FIHNPSLTVT VPIAPGESDL ENMNAEELSS DSDSEYSKVR LNRSSSSECS TVD NPLPGE GEEAEAEPMN SDEPEACFTD GCVRRFSCCQ VNIESGKGKI WWNIRKTCYK IVEHSWFESF IVLMILLSSG ALAF EDIYI ERKKTIKIIL EYADKIFTYI FILEMLLKWI AYGYKTYFTN AWCWLDFLIV DVSLVTLVAN TLGYSDLGPI KSLRT LRAL RPLRALSRFE GMRVVVNALI GAIPSIMNVL LVCLIFWLIF SIMGVNLFAG KFYECINTTD GSRFPASQVP NRSECF ALM NVSQNVRWKN LKVNFDNVGL GYLSLLQVAT FKGWTIIMYA AVDSVNVDKQ PKYEYSLYMY IYFVVFIIFG SFFTLNL FI GVIIDNFNQQ KKKLGGQDIF MTEEQKKYYN AMKKLGSKKP QKPIPRPGNK IQGCIFDLVT NQAFDISIMV LICLNMVT M MVEKEGQSQH MTEVLYWINV VFIILFTGEC VLKLISLRHY YFTVGWNIFD FVVVIISIVG MFLADLIETY FVSPTLFRV IRLARIGRIL RLVKGAKGIR TLLFALMMSL PALFNIGLLL FLVMFIYAIF GMSNFAYVKK EDGINDMFNF ETFGNSMICL FQITTSAGW DGLLAPILNS KPPDCDPKKV HPGSSVEGDC GNPSVGIFYF VSYIIISFLV VVNMYIAVIL ENFSVATEES T EPLSEDDF EMFYEVWEKF DPDATQFIEF SKLSDFAAAL DPPLLIAKPN KVQLIAMDLP MVSGDRIHCL DILFAFTKRV LG ESGEMDS LRSQMEERFM SANPSKVSYE PITTTLKRKQ EDVSATVIQR AYRRYRLRQN VKNISSIYIK DGDRDDDLLN KKD MAFDNV NENSSPEKTD ATSSTTSPPS YDSVTKPDKE KYEQDRTEKE DKGKDSKESK KAAALEVLFQ GPSKGEELFT GVVP ILVEL DGDVNGHKFS VRGEGEGDAT NGKLTLKFIC TTGKLPVPWP TLVTTLTYGV QCFSRYPDHM KRHDFFKSAM PEGYV QERT ISFKDDGTYK TRAEVKFEGD TLVNRIELKG IDFKEDGNIL GHKLEYNFNS HNVYITADKQ KNGIKANFKI RHNVED GSV QLADHYQQNT PIGDGPVLLP DNHYLSTQSV LSKDPNEKRD HMVLLEFVTA AGITHGMDEW SHPQFEKGGG SGGGSGG SA WSHPQFEK |
-分子 #2: Sodium channel subunit beta-1,Green fluorescent protein
分子 | 名称: Sodium channel subunit beta-1,Green fluorescent protein タイプ: protein_or_peptide / ID: 2 詳細: The fusion protein of Sodium channel, linker, GFP, and tag コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 54.472129 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MGRLLALVVG AALVSSACGG CVEVDSETEA VYGMTFKILC ISCKRRSETN AETFTEWTFR QKGTEEFVKI LRYENEVLQL EEDERFEGR VVWNGSRGTK DLQDLSIFIT NVTYNHSGDY ECHVYRLLFF ENYEHNTSVV KKIHIEVVDK ANRDMASIVS E IMMYVLIV ...文字列: MGRLLALVVG AALVSSACGG CVEVDSETEA VYGMTFKILC ISCKRRSETN AETFTEWTFR QKGTEEFVKI LRYENEVLQL EEDERFEGR VVWNGSRGTK DLQDLSIFIT NVTYNHSGDY ECHVYRLLFF ENYEHNTSVV KKIHIEVVDK ANRDMASIVS E IMMYVLIV VLTIWLVAEM IYCYKKIAAA TETAAQENAS EYLAITSESK ENCTGVQVAE AAALEVLFQG PSKGEELFTG VV PILVELD GDVNGHKFSV RGEGEGDATN GKLTLKFICT TGKLPVPWPT LVTTLTYGVQ CFSRYPDHMK RHDFFKSAMP EGY VQERTI SFKDDGTYKT RAEVKFEGDT LVNRIELKGI DFKEDGNILG HKLEYNFNSH NVYITADKQK NGIKANFKIR HNVE DGSVQ LADHYQQNTP IGDGPVLLPD NHYLSTQSVL SKDPNEKRDH MVLLEFVTAA GITHGMDEHH HHHHHHHHDY KDDDD K |
-分子 #3: Sodium channel subunit beta-2
分子 | 名称: Sodium channel subunit beta-2 / 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: ![]() |
分子量 | 理論値: 24.355859 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MHRDAWLPRP AFSLTGLSLF FSLVPPGRSM EVTVPATLNV LNGSDARLPC TFNSCYTVNH KQFSLNWTYQ ECNNCSEEMF LQFRMKIIN LKLERFQDRV EFSGNPSKYD VSVMLRNVQP EDEGIYNCYI MNPPDRHRGH GKIHLQVLME EPPERDSTVA V IVGASVGG ...文字列: MHRDAWLPRP AFSLTGLSLF FSLVPPGRSM EVTVPATLNV LNGSDARLPC TFNSCYTVNH KQFSLNWTYQ ECNNCSEEMF LQFRMKIIN LKLERFQDRV EFSGNPSKYD VSVMLRNVQP EDEGIYNCYI MNPPDRHRGH GKIHLQVLME EPPERDSTVA V IVGASVGG FLAVVILVLM VVKCVRRKKE QKLSTDDLKT EEEGKTDGEG NPDDGAK |
-分子 #5: 2-acetamido-2-deoxy-beta-D-glucopyranose
分子 | 名称: 2-acetamido-2-deoxy-beta-D-glucopyranose / タイプ: ligand / ID: 5 / コピー数: 5 / 式: NAG |
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分子量 | 理論値: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-分子 #6: (1~{Z})-~{N}-[2-methyl-3-[(~{E})-[6-[4-[[4-(trifluoromethyloxy)ph...
分子 | 名称: (1~{Z})-~{N}-[2-methyl-3-[(~{E})-[6-[4-[[4-(trifluoromethyloxy)phenyl]methoxy]piperidin-1-yl]-1~{H}-1,3,5-triazin-2-ylidene]amino]phenyl]ethanimidic acid タイプ: ligand / ID: 6 / コピー数: 1 / 式: G4I |
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分子量 | 理論値: 516.515 Da |
Chemical component information | ![]() ChemComp-G4I: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
緩衝液 | pH: 7.5 |
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凍結 | 凍結剤: ETHANE |
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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: 60.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
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): 2.5 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 |
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画像解析
初期モデル | モデルのタイプ: EMDB MAP EMDB ID: |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 3.09 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 158142 |
初期 角度割当 | タイプ: RANDOM ASSIGNMENT |
最終 角度割当 | タイプ: RANDOM ASSIGNMENT |