+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-43034 | |||||||||
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タイトル | Alpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 asymmetric state 1 | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | ION CHANNEL / MEMBRANE PROTEIN / NICOTINIC RECEPTOR | |||||||||
機能・相同性 | 機能・相同性情報 sensory processing / dendrite arborization / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / response to acetylcholine / acetylcholine-gated channel complex / acetylcholine-gated monoatomic cation-selective channel activity / regulation of amyloid fibril formation / short-term memory / positive regulation of CoA-transferase activity ...sensory processing / dendrite arborization / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / response to acetylcholine / acetylcholine-gated channel complex / acetylcholine-gated monoatomic cation-selective channel activity / regulation of amyloid fibril formation / short-term memory / positive regulation of CoA-transferase activity / dendritic spine organization / acetylcholine binding / chloride channel regulator activity / regulation of amyloid precursor protein catabolic process / acetylcholine receptor signaling pathway / positive regulation of amyloid-beta formation / negative regulation of amyloid-beta formation / plasma membrane raft / modulation of excitatory postsynaptic potential / response to amyloid-beta / positive regulation of excitatory postsynaptic potential / negative regulation of tumor necrosis factor production / toxic substance binding / monoatomic ion transport / positive regulation of protein metabolic process / monoatomic ion channel activity / positive regulation of long-term synaptic potentiation / cognition / response to nicotine / electron transport chain / synapse organization / calcium channel activity / memory / intracellular calcium ion homeostasis / positive regulation of angiogenesis / calcium ion transport / monoatomic ion transmembrane transport / amyloid-beta binding / postsynaptic membrane / postsynapse / positive regulation of MAPK cascade / periplasmic space / positive regulation of ERK1 and ERK2 cascade / electron transfer activity / learning or memory / response to hypoxia / neuron projection / iron ion binding / positive regulation of protein phosphorylation / positive regulation of cell population proliferation / heme binding / synapse / signal transduction / protein homodimerization activity / membrane / 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: 3.29 Å | |||||||||
データ登録者 | Burke SM / Noviello CM / Hibbs RE | |||||||||
資金援助 | 米国, 1件
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引用 | ジャーナル: Cell / 年: 2024 タイトル: Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation. 著者: Sean M Burke / Mariia Avstrikova / Colleen M Noviello / Nuriya Mukhtasimova / Jean-Pierre Changeux / Ganesh A Thakur / Steven M Sine / Marco Cecchini / Ryan E Hibbs / 要旨: The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological ...The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily. | |||||||||
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_43034.map.gz | 136.5 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-43034-v30.xml emd-43034.xml | 35.5 KB 35.5 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_43034_fsc.xml | 11.1 KB | 表示 | FSCデータファイル |
画像 | emd_43034.png | 57.2 KB | ||
Filedesc metadata | emd-43034.cif.gz | 6.8 KB | ||
その他 | emd_43034_additional_1.map.gz emd_43034_additional_2.map.gz emd_43034_additional_3.map.gz emd_43034_additional_4.map.gz emd_43034_additional_5.map.gz emd_43034_additional_6.map.gz emd_43034_additional_7.map.gz emd_43034_additional_8.map.gz emd_43034_additional_9.map.gz emd_43034_half_map_1.map.gz emd_43034_half_map_2.map.gz | 72.2 MB 136.8 MB 136.8 MB 72.3 MB 134.3 MB 134.1 MB 134.2 MB 69.2 MB 134.2 MB 134.1 MB 134.3 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-43034 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-43034 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_43034_validation.pdf.gz | 1.3 MB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_43034_full_validation.pdf.gz | 1.3 MB | 表示 | |
XML形式データ | emd_43034_validation.xml.gz | 19.8 KB | 表示 | |
CIF形式データ | emd_43034_validation.cif.gz | 25.4 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-43034 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-43034 | HTTPS FTP |
-関連構造データ
関連構造データ | 8v8cMC 8ut1C 8utbC 8uzjC 8v80C 8v82C 8v86C 8v88C 8v89C 8v8aC 8v8dC M: このマップから作成された原子モデル C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-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_43034.map.gz / 形式: CCP4 / 大きさ: 144.7 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: 0.825 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
+追加マップ: #9
+追加マップ: #8
+追加マップ: #7
+追加マップ: #6
+追加マップ: #5
+追加マップ: #4
+追加マップ: #3
+追加マップ: #2
+追加マップ: #1
+ハーフマップ: #2
+ハーフマップ: #1
-試料の構成要素
-全体 : Alpha7-nicotinic acetylcholine receptor time resolved bound to ep...
全体 | 名称: Alpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 asymmetric state 1 |
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要素 |
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-超分子 #1: Alpha7-nicotinic acetylcholine receptor time resolved bound to ep...
超分子 | 名称: Alpha7-nicotinic acetylcholine receptor time resolved bound to epibatidine and PNU-120596 asymmetric state 1 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: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrom...
分子 | 名称: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562 タイプ: protein_or_peptide / ID: 1 詳細: 351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351- ...詳細: 351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage),351-353 (linker) 354-460 (SOLUBLE CYTOCHROME B562 FUSION) 551-558 (strep tag II) 559-571 (linker) 572-579 (strep tag II) 580-582 (linker) 583-599 (T2A self cleaving peptide post cleavage) コピー数: 5 / 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: 67.220797 KDa |
組換発現 | 生物種: Homo sapiens (ヒト) |
配列 | 文字列: EFQRKLYKEL VKNYNPLERP VANDSQPLTV YFSLSLLQIM DVDEKNQVLT TNIWLQMSWT DHYLQWNVSE YPGVKTVRFP DGQIWKPDI LLYNSADERF DATFHTNVLV NSSGHCQYLP PGIFKSSCYI DVRWFPFDVQ HCKLKFGSWS YGGWSLDLQM Q EADISGYI ...文字列: EFQRKLYKEL VKNYNPLERP VANDSQPLTV YFSLSLLQIM DVDEKNQVLT TNIWLQMSWT DHYLQWNVSE YPGVKTVRFP DGQIWKPDI LLYNSADERF DATFHTNVLV NSSGHCQYLP PGIFKSSCYI DVRWFPFDVQ HCKLKFGSWS YGGWSLDLQM Q EADISGYI PNGEWDLVGI PGKRSERFYE CCKEPYPDVT FTVTMRRRTL YYGLNLLIPC VLISALALLV FLLPADSGEK IS LGITVLL SLTVFMLLVA EIMPATSDSV PLIAQYFAST MIIVGLSVVV TVIVLQYHHH DPDGGKMPKW TRVILLNWCA WFL RMKRPG EDKVRPACQH KQRRCSLACG RMACAGAMAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPP KLEDK SPDSPEMKDF RHGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLSPTHD EHLLHGGQPP EGDPD LAKI LEEVRYIANR FRCQDESEAV CSEWKFAACV VDRLCLMAFS VFTIICTIGI LMSAPNFVEA VSKDFAWSHP QFEKGG GSG GGSGGSSAWS HPQFEKGSGE GRGSLLTCGD VEENPG UniProtKB: Neuronal acetylcholine receptor subunit alpha-7, Soluble cytochrome b562 |
-分子 #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
分子 | 名称: 2-acetamido-2-deoxy-beta-D-glucopyranose / タイプ: ligand / ID: 3 / コピー数: 10 / 式: NAG |
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分子量 | 理論値: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-分子 #4: EPIBATIDINE
分子 | 名称: EPIBATIDINE / タイプ: ligand / ID: 4 / コピー数: 5 / 式: EPJ |
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分子量 | 理論値: 208.687 Da |
Chemical component information | ChemComp-EPJ: |
-分子 #5: N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea
分子 | 名称: N-(5-Chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)-urea タイプ: ligand / ID: 5 / コピー数: 5 / 式: I34 |
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分子量 | 理論値: 311.721 Da |
Chemical component information | ChemComp-I34: |
-分子 #6: CALCIUM ION
分子 | 名称: CALCIUM ION / タイプ: ligand / ID: 6 / コピー数: 3 / 式: CA |
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分子量 | 理論値: 40.078 Da |
-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
濃度 | 6.5 mg/mL |
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緩衝液 | pH: 7.4 |
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 K3 (6k x 4k) / 平均電子線量: 40.0 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): 2.0 µm / 最小 デフォーカス(公称値): 0.5 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |