EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Structural insights into human organic cation transporter 1 transport and inhibition.
ジャーナル・号・ページ	Cell Discov, Vol. 10, Issue 1, Page 30, Year 2024
掲載日	2024年3月15日
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 /
PubMed 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.
リンク	Cell Discov / PubMed:38485705 / PubMed Central
手法	EM (単粒子)
解像度	2.98 - 4.14 Å
構造データ	36651 8jts EMDB-36651, PDB-8jts: hOCT1 in complex with metformin in outward open conformation 手法: EM (単粒子) / 解像度: 4.14 Å 36652 8jtt EMDB-36652, PDB-8jtt: hOCT1 in complex with metformin in outward occluded conformation 手法: EM (単粒子) / 解像度: 3.87 Å 36653 8jtv EMDB-36653, PDB-8jtv: hOCT1 in complex with metformin in inward occluded conformation 手法: EM (単粒子) / 解像度: 3.77 Å 36654 8jtw EMDB-36654, PDB-8jtw: hOCT1 in complex with nb5660 in inward facing partially open 1 conformation 手法: EM (単粒子) / 解像度: 3.23 Å 36655 8jtx EMDB-36655, PDB-8jtx: hOCT1 in complex with nb5660 in inward facing fully open conformation 手法: EM (単粒子) / 解像度: 3.28 Å 36656 8jty EMDB-36656, PDB-8jty: hOCT1 in complex with nb5660 in inward facing partially open 2 conformation 手法: EM (単粒子) / 解像度: 3.26 Å 36657 8jtz EMDB-36657, PDB-8jtz: hOCT1 in complex with spironolactone in outward facing partially occluded conformation 手法: EM (単粒子) / 解像度: 3.27 Å 36658 8ju0 EMDB-36658, PDB-8ju0: hOCT1 in complex with spironolactone in inward facing occluded conformation 手法: EM (単粒子) / 解像度: 2.98 Å
化合物	ChemComp-MF8: Metformin / メトホルミン / 薬剤, 抗精神病薬YM ChemComp-SNL: SPIRONOLACTONE / スピロノラクトン / 薬剤YM
由来	homo sapiens (ヒト) lama glama (ラマ)
キーワード	MEMBRANE PROTEIN / SLC / transporter