+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-8941 | |||||||||
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タイトル | Cryo-EM structure of the ts2-inactive human serotonin transporter in complex with paroxetine and 15B8 Fab and 8B6 ScFv | |||||||||
マップデータ | sharpened map | |||||||||
試料 |
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キーワード | paroxetine / antidepressant / human serotonin transporter / Fab / TRANSPORT PROTEIN-IMMUNE SYSTEM complex | |||||||||
機能・相同性 | 機能・相同性情報 negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / serotonergic synapse / Serotonin clearance from the synaptic cleft / positive regulation of serotonin secretion / cocaine binding / negative regulation of synaptic transmission, dopaminergic / sperm ejaculation / serotonin:sodium:chloride symporter activity / sodium ion binding ...negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / serotonergic synapse / Serotonin clearance from the synaptic cleft / positive regulation of serotonin secretion / cocaine binding / negative regulation of synaptic transmission, dopaminergic / sperm ejaculation / serotonin:sodium:chloride symporter activity / sodium ion binding / cellular response to cGMP / enteric nervous system development / negative regulation of organ growth / serotonin uptake / neurotransmitter transmembrane transporter activity / serotonin binding / monoamine transmembrane transporter activity / monoamine transport / conditioned place preference / vasoconstriction / brain morphogenesis / antiporter activity / neurotransmitter transport / syntaxin-1 binding / amino acid transport / nitric-oxide synthase binding / membrane depolarization / behavioral response to cocaine / social behavior / negative regulation of neuron differentiation / sodium ion transmembrane transport / endomembrane system / monoatomic cation channel activity / positive regulation of cell cycle / cellular response to retinoic acid / response to nutrient / platelet aggregation / memory / response to toxic substance / circadian rhythm / actin filament binding / integrin binding / response to estradiol / presynaptic membrane / postsynaptic membrane / response to hypoxia / endosome membrane / neuron projection / response to xenobiotic stimulus / membrane raft / focal adhesion / synapse / positive regulation of gene expression / identical protein binding / plasma membrane 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) / Mus musculus (ハツカネズミ) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 4.3 Å | |||||||||
データ登録者 | Coleman JA / Yang D | |||||||||
資金援助 | 米国, 2件
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引用 | ジャーナル: Nature / 年: 2019 タイトル: Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. 著者: Jonathan A Coleman / Dongxue Yang / Zhiyu Zhao / Po-Chao Wen / Craig Yoshioka / Emad Tajkhorshid / Eric Gouaux / 要旨: The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons. Major depression and anxiety ...The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons. Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors-small molecules that competitively block substrate binding and thereby prolong neurotransmitter action. The dopamine and noradrenaline transporters, together with SERT, are members of the neurotransmitter sodium symporter (NSS) family. The transport activities of NSSs can be inhibited or modulated by cocaine and amphetamines, and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder. Studies of bacterial NSS homologues-including LeuT-have shown how their transmembrane helices (TMs) undergo conformational changes during the transport cycle, exposing a central binding site to either side of the membrane. However, the conformational changes associated with transport in NSSs remain unknown. To elucidate structure-based mechanisms for transport in SERT we investigated its complexes with ibogaine, a hallucinogenic natural product with psychoactive and anti-addictive properties. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors. Here we report cryo-electron microscopy structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations. Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TM1a and the partial unwinding of TM5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm. These structures define the structural rearrangements that occur from the outward-open to inward-open conformations, and provide insight into the mechanism of neurotransmitter transport and ibogaine inhibition. | |||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_8941.map.gz | 49 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-8941-v30.xml emd-8941.xml | 27.9 KB 27.9 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_8941_fsc.xml | 9.4 KB | 表示 | FSCデータファイル |
画像 | emd_8941.png | 84.6 KB | ||
マスクデータ | emd_8941_msk_1.map | 52.7 MB | マスクマップ | |
Filedesc metadata | emd-8941.cif.gz | 6.7 KB | ||
その他 | emd_8941_additional.map.gz emd_8941_half_map_1.map.gz emd_8941_half_map_2.map.gz | 48.6 MB 6.1 MB 6.1 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-8941 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-8941 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_8941_validation.pdf.gz | 810.7 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_8941_full_validation.pdf.gz | 810.2 KB | 表示 | |
XML形式データ | emd_8941_validation.xml.gz | 15.1 KB | 表示 | |
CIF形式データ | emd_8941_validation.cif.gz | 19.8 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-8941 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-8941 | 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_8941.map.gz / 形式: CCP4 / 大きさ: 52.7 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | sharpened map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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: 1.044 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-マスク #1
ファイル | emd_8941_msk_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-追加マップ: unsharpened map
ファイル | emd_8941_additional.map | ||||||||||||
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注釈 | unsharpened map | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: half map 1
ファイル | emd_8941_half_map_1.map | ||||||||||||
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注釈 | half map 1 | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: half map 2
ファイル | emd_8941_half_map_2.map | ||||||||||||
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注釈 | half map 2 | ||||||||||||
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 : Human serotonin transporter in complex with Fab/Fv bound to paroxetine
+超分子 #1: Human serotonin transporter in complex with Fab/Fv bound to paroxetine
+超分子 #2: serotonin transporter
+超分子 #3: 8B6 ScFv
+超分子 #4: 15B8 Fab
+分子 #1: Sodium-dependent serotonin transporter
+分子 #2: 8B6 antibody single chain
+分子 #3: 15B8 antibody heavy chain
+分子 #4: 15B8 antibody light chain
+分子 #6: Paroxetine
+分子 #7: 2-acetamido-2-deoxy-beta-D-glucopyranose
-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: 8 |
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グリッド | 詳細: unspecified |
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: 50.0 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 |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |