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データを開く
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基本情報
登録情報 | データベース: PDB / ID: 8jtx | ||||||
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タイトル | hOCT1 in complex with nb5660 in inward facing fully open conformation | ||||||
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![]() | MEMBRANE PROTEIN / SLC / transporter | ||||||
機能・相同性 | ![]() 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 / basal plasma membrane / xenobiotic metabolic process / presynapse / basolateral plasma membrane / apical plasma membrane / identical protein binding / membrane / plasma membrane 類似検索 - 分子機能 | ||||||
生物種 | ![]() ![]() ![]() | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.28 Å | ||||||
![]() | 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 | ![]()
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![]() | ![]() 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. | ||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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PDBx/mmCIF形式 | ![]() | 119.7 KB | 表示 | ![]() |
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PDB形式 | ![]() | 89.9 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
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-関連構造データ
関連構造データ | ![]() 36655MC ![]() 8jtsC ![]() 8jttC ![]() 8jtvC ![]() 8jtwC ![]() 8jtyC ![]() 8jtzC ![]() 8ju0C M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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集合体
登録構造単位 | ![]()
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要素
#1: タンパク質 | 分子量: 62569.164 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: O15245 |
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#2: 抗体 | 分子量: 14421.984 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() ![]() |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: human organic cation transporter in compelx wtih nb5660 in inward facing fully open conformation タイプ: COMPLEX / Entity ID: all / 由来: MULTIPLE SOURCES |
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分子量 | 実験値: NO |
由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() ![]() |
緩衝液 | pH: 8 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
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電子顕微鏡撮影
顕微鏡 | モデル: FEI TITAN |
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電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1500 nm / 最小 デフォーカス(公称値): 1100 nm |
撮影 | 電子線照射量: 50 e/Å2 フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) |
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解析
CTF補正 | タイプ: NONE | ||||||||||||||||||||||||
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3次元再構成 | 解像度: 3.28 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 110551 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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