8SC2

Human OCT1 bound to diltiazem in inward-open conformation

8SC2 の概要

• エントリーDOI: 10.2210/pdb8sc2/pdb
• EMDBエントリー: 40335
• 分子名称: Solute carrier family 22 member 1, Diltiazem (2 entities in total)
• 機能のキーワード: membrane protein, mfs, drug transporter, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 59581.94

構造登録者

Zeng, Y.C.,Sobti, M.,Stewart, A.G. (登録日: 2023-04-04, 公開日: 2023-10-18, 最終更新日: 2025-05-28)

主引用文献

Zeng, Y.C.,Sobti, M.,Quinn, A.,Smith, N.J.,Brown, S.H.J.,Vandenberg, J.I.,Ryan, R.M.,O'Mara, M.L.,Stewart, A.G.
Structural basis of promiscuous substrate transport by Organic Cation Transporter 1.
Nat Commun, 14:6374-6374, 2023

PubMed Abstract: Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1.

PubMed: 37821493
DOI: 10.1038/s41467-023-42086-9

実験手法

ELECTRON MICROSCOPY (3.36 Å)