+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-36658 | |||||||||
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タイトル | hOCT1 in complex with spironolactone in inward facing occluded conformation | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | SLC / transporter / MEMBRANE PROTEIN | |||||||||
機能・相同性 | 機能・相同性情報 secondary active organic cation transmembrane transporter activity / putrescine transmembrane transporter activity / (R)-carnitine transmembrane transporter activity / acyl carnitine transmembrane transport / pyrimidine nucleoside transmembrane transporter activity / acetylcholine transmembrane transporter activity / acetylcholine transport / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity ...secondary active organic cation transmembrane transporter activity / putrescine transmembrane transporter activity / (R)-carnitine transmembrane transporter activity / acyl carnitine transmembrane transport / pyrimidine nucleoside transmembrane transporter activity / acetylcholine transmembrane transporter activity / acetylcholine transport / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity / organic cation transport / quaternary ammonium group transport / epinephrine transport / thiamine transmembrane transport / purine-containing compound transmembrane transport / spermidine transport / thiamine transmembrane transporter activity / Organic cation transport / organic cation transmembrane transporter activity / putrescine transport / thiamine transport / dopamine uptake / metanephric proximal tubule development / prostaglandin transport / norepinephrine:sodium symporter activity / prostaglandin transmembrane transporter activity / toxin transmembrane transporter activity / Abacavir transmembrane transport / Norepinephrine Neurotransmitter Release Cycle / dopamine:sodium symporter activity / norepinephrine transport / serotonin uptake / neurotransmitter transmembrane transporter activity / dopamine transport / establishment or maintenance of transmembrane electrochemical gradient / organic anion transmembrane transporter activity / xenobiotic transport across blood-brain barrier / monoamine transmembrane transporter activity / Neurotransmitter clearance / Na+/Cl- dependent neurotransmitter transporters / monoamine transport / Ciprofloxacin ADME / xenobiotic transport / cellular detoxification / neurotransmitter transport / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / lateral plasma membrane / xenobiotic metabolic process / basal plasma membrane / presynapse / basolateral plasma membrane / apical plasma membrane / identical protein binding / 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: 2.98 Å | |||||||||
データ登録者 | Zhang S / Zhu A / Kong F / Chen J / Lan B / He G / Gao K / Cheng L / Yan C / Chen L / Liu X | |||||||||
資金援助 | 中国, 1件
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引用 | ジャーナル: Cell Discov / 年: 2024 タイトル: Structural insights into human organic cation transporter 1 transport and inhibition. 著者: Shuhao Zhang / Angqi Zhu / Fang Kong / Jianan Chen / Baoliang Lan / Guodong He / Kaixuan Gao / Lili Cheng / Xiaoou Sun / Chuangye Yan / Ligong Chen / Xiangyu Liu / 要旨: The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism ...The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism and drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics of many drugs, making interactions with hOCT1 a key consideration in novel drug development and drug-drug interactions. Notably, metformin, the frontline medication for type 2 diabetes, is a prominent hOCT1 substrate. Conversely, hOCT1 can be inhibited by agents such as spironolactone, a steroid analog inhibitor of the aldosterone receptor, necessitating a deep understanding of hOCT1-drug interactions in the development of new pharmacological treatments. Despite extensive study, specifics of hOCT1 transport and inhibition mechanisms remain elusive at the molecular level. Here, we present cryo-electron microscopy structures of the hOCT1-metformin complex in three distinct conformational states - outward open, outward occluded, and inward occluded as well as substrate-free hOCT1 in both partially and fully open states. We also present hOCT1 in complex with spironolactone in both outward and inward facing conformations. These structures provide atomic-level insights into the dynamic metformin transfer process via hOCT1 and the mechanism by which spironolactone inhibits it. Additionally, we identify a 'YER' motif critical for the conformational flexibility of hOCT1 and likely other SLC22 family transporters. Our findings significantly advance the understanding of hOCT1 molecular function and offer a foundational framework for the design of new therapeutic agents targeting this transporter. | |||||||||
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_36658.map.gz | 28.7 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-36658-v30.xml emd-36658.xml | 14.4 KB 14.4 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_36658.png | 54.6 KB | ||
Filedesc metadata | emd-36658.cif.gz | 5.6 KB | ||
その他 | emd_36658_half_map_1.map.gz emd_36658_half_map_2.map.gz | 28.3 MB 28.3 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-36658 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36658 | HTTPS FTP |
-関連構造データ
関連構造データ | 8ju0MC 8jtsC 8jttC 8jtvC 8jtwC 8jtxC 8jtyC 8jtzC 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_36658.map.gz / 形式: CCP4 / 大きさ: 30.5 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 1.0825 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_36658_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_36658_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 : human organic cation transporter in compelx wtih spironolactone i...
全体 | 名称: human organic cation transporter in compelx wtih spironolactone in inward facing occludded conformation |
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要素 |
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-超分子 #1: human organic cation transporter in compelx wtih spironolactone i...
超分子 | 名称: human organic cation transporter in compelx wtih spironolactone in inward facing occludded conformation 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: Solute carrier family 22 member 1
分子 | 名称: Solute carrier family 22 member 1 / 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: 62.569164 KDa |
組換発現 | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
配列 | 文字列: MPTVDDILEQ VGESGWFQKQ AFLILCLLSA AFAPICVGIV FLGFTPDHHC QSPGVAELSQ RCGWSPAEEL NYTVPGLGPA GEAFLGQCR RYEVDWNQSA LSCVDPLASL ATNRSHLPLG PCQDGWVYDT PGSSIVTEFN LVCADSWKLD LFQSCLNAGF L FGSLGVGY ...文字列: MPTVDDILEQ VGESGWFQKQ AFLILCLLSA AFAPICVGIV FLGFTPDHHC QSPGVAELSQ RCGWSPAEEL NYTVPGLGPA GEAFLGQCR RYEVDWNQSA LSCVDPLASL ATNRSHLPLG PCQDGWVYDT PGSSIVTEFN LVCADSWKLD LFQSCLNAGF L FGSLGVGY FADRFGRKLC LLGTVLVNAV SGVLMAFSPN YMSMLLFRLL QGLVSKGNWM AGYTLITEFV GSGSRRTVAI MY QMAFTVG LVALTGLAYA LPHWRWLQLA VSLPTFLFLL YYWCVPESPR WLLSQKRNTE AIKIMDHIAQ KNGKLPPADL KML SLEEDV TEKLSPSFAD LFRTPRLRKR TFILMYLWFT DSVLYQGLIL HMGATSGNLY LDFLYSALVE IPGAFIALIT IDRV GRIYP MAMSNLLAGA ACLVMIFISP DLHWLNIIIM CVGRMGITIA IQMICLVNAE LYPTFVRNLG VMVCSSLCDI GGIIT PFIV FRLREVWQAL PLILFAVLGL LAAGVTLLLP ETKGVALPET MKDAENLGRK AKPKENTIYL KVQTSEPSGT EDQVDP RLI DGK UniProtKB: Solute carrier family 22 member 1 |
-分子 #2: SPIRONOLACTONE
分子 | 名称: SPIRONOLACTONE / タイプ: ligand / ID: 2 / コピー数: 1 / 式: SNL |
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分子量 | 理論値: 416.573 Da |
Chemical component information | ChemComp-SNL: |
-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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凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN |
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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: 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 / 最大 デフォーカス(公称値): 1.5 µm / 最小 デフォーカス(公称値): 1.1 µm |
-画像解析
初期モデル | モデルのタイプ: NONE |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.98 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 602445 |
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |